Oxidation-stabilized tamper-resistant dosage form

ABSTRACT

A thermoformed pharmaceutical dosage form having a breaking strength of at least 300 N, said dosage form comprising
         a pharmacologically active ingredient (A),   a free physiologically acceptable acid (B) in an amount of from 0.001 wt.-% to 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form, and   a polyalkylene oxide (C) having a weight average molecular weight M w  of at least 200,000 g/mol.

This application is a continuation of Ser. No. 15/901,063, filed Feb.21, 2018, now pending which is a division of U.S. patent applicationSer. No. 14/841,829, filed Sep. 1, 2015, now issued as U.S. Pat. No.9,925,146, issued date Mar. 27, 2018, which is a continuation of U.S.patent application Ser. No. 14/192,916, filed Feb. 28, 2014, abandoned,which is a continuation of U.S. patent application Ser. No. 13/343,846,filed Jan. 5, 2012, abandoned, which is, in turn, a continuation ofInternational Patent Application No. PCT/EP2010/004461, filed Jul. 21,2010, which claims priority of European Patent Application No.09009480.6, filed Jul. 22, 2009, the contents of both of whichapplications are incorporated herein by reference.

The invention relates to a pharmaceutical dosage form which isstabilized towards oxidation.

Many pharmacologically active compounds have a potential of being abusedand thus, are advantageously provided in form of tamper resistantpharmaceutical dosage forms. Prominent examples of suchpharmacologically active compounds are opioids.

It is known that abusers crush conventional tablets, which containopioids, to defeat the time-release “micro-encapsulation” and theningest the resulting powder orally, intranasally, rectally, or byinjection.

Various concepts for the avoidance of drug abuse have been developed.One concept relies on the mechanical properties of the pharmaceuticaldosage forms, particularly an increased breaking strength (resistance tocrushing). The major advantage of such pharmaceutical dosage forms isthat comminuting, particularly pulverization, by conventional means,such as grinding in a mortar or fracturing by means of a hammer, isimpossible or at least substantially impeded.

Such pharmaceutical dosage forms are useful for avoiding drug abuse ofthe pharmacologically active compound contained therein, as they may notbe powdered by conventional means and thus, cannot be administered inpowdered from, e.g. nasally.

The mechanical properties, particularly the high breaking strength ofthese pharmaceutical dosage forms renders them tamper resistant. In thecontext of such tamper resistant pharmaceutical dosage forms it can bereferred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO2006/082097, WO 2006/082099, and WO 2008/107149.

These tamper resistant pharmaceutical dosage forms contain a syntheticor natural polymer, most often a high molecular weight polyethyleneoxide, as matrix material.

Polyethylene oxides, like other aliphatic ethers, can undergoautoxidation in presence of oxygen to form hydroperoxides (see forinstance C. W. McGary Jr., J. Polymer Sci., 2003, 46, 51-57). Subsequentradical reactions of the resulting peroxides lead to chain scission.These natural aging processes are catalyzed by other oxidation agentsand are further accelerated by UV light and/or elevated temperatures.The oxidative degradation process is highly dependent on the molecularweight. High molecular weight polyethylene oxides are especially proneto autoxidation processes and degrade more rapidly than lower molecularweight polyethylene oxides.

Also oxidative sensitive pharmacologically active ingredients, such asopioids like oxymorphone, hydromorphone, and oxycodone, are sensitivetowards oxidative degradation and decomposition processes.

As a result of the degradation processes, the properties of a dosageform containing oxidatively degradable matrix material and/or oxidativesensitive pharmacologically active ingredients may seriously beaffected. For example, loss of content of the pharmacologically activeingredient as well as discoloration, decreased mechanical strength andaccelerated drug release due to shortened polymer chains are likely tooccur. Especially the breaking strength is highly dependent on themolecular weight of the polyalkylene oxide contained in the dosage formand thus directly influenced by chain scission processes.

Oxidation may be caused by molecular oxygen or by radicals or peroxidesgenerated by compounds that come into close proximity with theseoxidation-sensitive matrix materials and/or pharmacologically activeingredients.

Pharmaceutical excipients as such, e.g. polyethylene glycols, may causeor catalyze oxidative degradation, for example in the course of theprocess for manufacturing the pharmaceutical dosage forms. Further,molecular oxygen may generate said radicals or peroxides.

Typically, decomposition is monitored in standard storage stabilitytests e.g. under accelerated storage conditions, such as 40° C./75% rel.humidity. Under these conditions, degradation and decompositiontypically proceeds faster than under ambient conditions. The drugapproving authorities, such as CHMP and FDA, and internationalharmonization unions, such as ICH, have set standard storage stabilitythresholds which have to be met in order to get a pharmaceutical dosageform approved.

Particular problems arise when such pharmaceutical dosage formscomprising oxidative degradable matrix materials and/oroxidation-sensitive pharmacologically active ingredients need to beexposed to elevated temperatures in the course of the manufacturingprocess, such as hot-melt extrusion, film coating and the like. Underthese conditions said compounds are even more sensitive towardsoxidation. For example, several known processes for the manufacture ofpharmaceutical dosage forms having an increased breaking strengthrequire that a pharmaceutical composition containing thepharmacologically active ingredient is subjected to a specific amount ofpressure at a specific elevated temperature for a specific period oftime. Depending on the constituents of the pharmaceutical compositionand their amounts, temperature, pressure and time may be varied withincertain limits. However, if the minimal requirements are not satisfied,the breaking strength of the resultant pharmaceutical dosage form is toolow.

In consequence, some conventional processes for the manufacture ofpharmaceutical dosage forms, particularly for pharmaceutical dosageforms having an increased breaking strength, require comparatively harshprocess conditions and thus, are so far not applicable foroxidation-sensitive matrix materials and/or pharmacologically activeingredients, e. g. opioids. In particular, chain rupture ofpharmaceutical excipients such as polyethylene oxide during hot meltextrusion risks the formation of free radicals thereby furtherincreasing the oxidative stress.

Lower dosages of oxidation-sensitive pharmacologically activeingredients often show a higher percentage of oxidative degradation anddecomposition than higher dosages. Thus, as far as storage stability isconcerned, pharmaceutical dosage forms containing lower dosages ofoxidation-sensitive pharmacologically active ingredients need particularattention.

The effect of oxidation mechanisms and chemical interactions onstability of polymeric systems for amorphous Δ⁹-tetrahydrocannabinol (anon-opioid) produced by a hot-melt method is described in M. Munjal etal., J. Pharm. Sciences, 95(11), 2006, 2473-85. The study demonstratedfor this highly unstable drug a complex nature of interactions includingdrug-excipient compatibility, use of antioxidants, cross-linking inpolymeric matrixes, micro environment pH, and moisture effect.

K. C. Waterman et al., Pharm. Develop. Tech. 7(1), 2002, 1-32 reviewsthe stabilization of pharmaceuticals to oxidative degradation. Variousmethods for reducing oxidation are recommended. The authors concludethat in the end, every drug presents a unique situation.

WO 2008/107149 discloses oral dosage forms having an increased breakingstrength that may contain redox stabilizers such as complexing agents,e.g. EDTA.

WO 2008/086804 relates to controlled release compositions containing amatrix composition comprising a) polymer or a mixture of polymers, b) anactive drug substance and optionally c) one or more pharmaceuticallyacceptable excipients that is without alcohol induced dose dumping andhave excellent properties with respect to avoiding drug abuse.Preferably, the composition is resistant to isolate and/or dissolve theactive drug substance from the composition by crushing, melting and/orethanol extraction, whereby the composition is resistant to drug abuse.Citric acid may be present as flavouring agent. Example 2 relates to acomposition containing 7 wt.-% of citric acid.

WO 2008/148798 discloses an layered extended release composition forprolonged effect and a way to ensure prolonged effect e.g. once dailyadministration is to ensure optimal absorption of the active substancethough the gastrointestinal tract i.e. from the stomach to rectum.

There is no general concept to successfully suppress oxidativedegradation of oxidative degradable matrix materials such aspolyethylene oxide and oxidation-sensitive drugs in pharmaceuticaldosage forms. The complex individual oxidation mechanisms that arerelevant for a particular matrix material or drug as well as theplurality of possible factors that have an influence on oxidationprocesses require extensive investigations in each particular casetaking into account the particular circumstances. Possible methods todefend a dosage form from oxidative degradation processes are theaddition of antioxidants, storage under an inert atmosphere or theapplication of an oxygen barrier film coating. The latter two methodsare, however, difficult to apply during all stages of the manufacturingprocess.

It is further known that the oxidative degradation processes areespecially accelerated when the dosage forms are exposed to harshprocess conditions, e. g. during the manufacturing process. For example,high molecular weight polyethylene oxide tends to degrade upon hot-meltextrusion. Polymer degradation, however, may result in an uncontrolledrelease profile, particularly when the active ingredient is embedded ina matrix of the polyethylene oxide, and this might be another cause foroxidative degradation of the pharmacologically active ingredient byradicals. When adding suitable excipients in order to stabilize the highmolecular weight polyethylene oxide, such as α-tocopherol, it should betaken into considerations that said excipients in turn may have adetrimental effect on the stability of other ingredients of thepharmaceutical dosage, e.g. of the pharmacologically active compound.

It is an object of the present invention to provide tamper-resistantpharmaceutical dosage forms containing pharmacologically activeingredients, particularly oxidation-sensitive opioids, that haveadvantages over the pharmaceutical dosage forms of the prior art. Thepharmaceutical dosage forms should have improved storage stability, sothat they may contain oxidation-sensitive opioids even at comparativelylow doses. Further, it should be possible to prepare the pharmaceuticaldosage forms by conventional processes under conventional conditionssuch as elevated temperature and pressure (e.g. in the course ofthermoforming by hot-melt extrusion).

This object has been solved by the subject-matter of the patent claims.

The invention relates to a thermoformed pharmaceutical dosage formhaving a breaking strength of at least 300 N and comprising

-   -   a pharmacologically active ingredient (A),    -   a free physiologically acceptable acid (B) in an amount of from        0.001 to 5.0 wt.-%, based on the total weight of the        pharmaceutical dosage form, and    -   a polyalkylene oxide (C) having a weight average molecular        weight M_(w) of at least 200,000 g/mol.

It has been surprisingly found that pharmaceutical dosage formscontaining oxidatively degradable polymers such as high molecular weightpolyethylene oxide can be prevented from oxidative degradation anddecomposition processes by the presence of suitable amounts of acid (B)in the pharmaceutical dosage forms according to the invention. By meansof this method, it has been surprisingly found, that the specificmaterial properties of the dosage form according to the invention suchas the breaking strength and the retarded release of the activeingredient may be retained for a longer storage period.

Thus, the increased storage stability of the polymer matrix is reflectedby an improved stability of the in vitro release profile upon storageand/or by an improved stability of the mechanical properties of thedosage forms. Both properties essentially rely upon the polymer matrixmaterial.

It has further been surprisingly found that certain morphinanderivatives such as oxymorphone are oxidatively degraded to N-oxides(e.g., oxymorphone-N-oxide, N-oxides in general are often said to betoxic and possibly cancerogenic) upon manufacture and storage of thecorresponding dosage forms and that the formation of said N-oxides andother decomposition products can be suppressed by the presence ofsuitable amounts of acid (B) in the pharmaceutical dosage formsaccording to the invention.

Thus, the increased storage stability of the pharmacologically activeingredient (A) is reflected by a decrease of impurities, if any, and areduced decrease of the pharmacologically active ingredient (A) uponstorage, if any, respectively.

While it is not intended to be bound to any theory, acid (B) seems toinfluence the micro-pH value of the pharmaceutical formulation therebysomehow increasing its storage stability. Thus, as far as the storagestability of the pharmacologically active ingredient is concerned, thestabilizing effect of acid (B) might correlate with the pK_(A)-value ofthe oxidation-sensitive drug. For example the pK_(A)-value ofoxymorphone is 8.3. Conventional formulations of oxymorphone, which aretamper resistant due to their increased breaking strength but which donot show the desired shelf life, give a pH value of about 7.5 when beingdispersed in water. Under these conditions, a considerable amount of theoxymorphone is present as a free base (i.e., is not protonated), whichmight be more sensitive towards oxidation than the (protonated) saltform.

This concept is further supported by the fact that in the absence ofacid (B), the dosage forms tend to have a yellowish, beige color, whilethe presence of acid (B) leads to whiter, e.g. colorless tablets. Thus,the presence of acid (B) might decrease the pH value within the dosageform thereby improving drug and/or polymer resistance towards oxidativedegradation.

It appears that the acidic nature of acid (B) is responsible for itsstabilizing effect but not any other properties. This concept issupported by the fact that inorganic as well as organic acids bothenhance the storage stability of the dosage form.

It has been surprisingly found that pharmaceutical excipients which areconventionally used in order to improve drug resistance towardsoxidative degradation, particularly certain antioxidants, e.g.,α-tocopherol, can be contra-productive and rather deteriorate thanimprove drug resistance towards oxidative degradation.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the in vitro release profile of pharmaceutical dosage formsaccording to inventive examples L₁ and L₃ and comparative examples L₂and L₄.

The pharmaceutical dosage form according to the invention isthermoformed, preferably by extrusion, although also other methods ofthermoforming may be used in order to manufacture the pharmaceuticaldosage form according to the invention such as press-molding at elevatedtemperature or heating of tablets that were manufactured by conventionalcompression in a first step and then heated above the softeningtemperature of the polymer in the tablet in a second step to form hardtablets. In this regards, thermoforming means the forming or molding ofa mass after the application of heat. In a preferred embodiment, thepharmaceutical dosage form is thermoformed by hot-melt extrusion.

Preferably, the pharmaceutical dosage form is a monolithic mass. Thepharmaceutical dosage form is preferably prepared by hot-melt extrusion.The melt extruded strands are preferably cut into monoliths, which arethen preferably formed into tablets. In this regard, the term “tablets”is preferably not to be understood as dosage forms being made bycompression of powder or granules (compressi) but rather, as shapedextrudates.

The pharmaceutical dosage form according to the invention contains, ascomponent (A), a pharmacologically active ingredient (A), preferably anoxidation-sensitive pharmacologically active ingredient. For the purposeof the specification, the term pharmacologically active ingredient (A)also includes the free base and the physiologically acceptable saltsthereof.

For the purpose of the specification, the term oxidation-sensitivepharmacologically active ingredient includes all pharmacologicallyactive ingredients that contain one or more functional group which isoxidized during the oxidative degradation process.

Functional groups whose oxidation may cause a pharmacologically activeingredient to be instable towards oxidation, are double bonds, as wellas aldehyde, keto, hydroxyl groups, ether, endiol, phenol and aminogroups.

The dosage form according to the invention particularly preferablycontains one or more pharmacologically active ingredients (A) selectedfrom the group consisting of

-   -   agents for the treatment and prevention of diseases of the        alimentary system and metabolism [A]; in particular        stomatological preparations [A01], agents for the treatment and        prevention of acid-related disorders [A02], agents for the        treatment and prevention of functional gastrointestinal tract        disorders [A03], serotonin 5HT3 antagonists [A04AA],        antihistamine preparations [A04AB], agents for bile and liver        therapy [A05], laxatives [A06], intestinal antiinfectives        [A07A], intestinal adsorbents [A07B], electrolytes with        carbohydrates [A07C], intestinal antiinflammatory agents [A07E],        microbial antidiarrhoeals [A07F], digestives including enzymes        [A09], drugs used in diabetes [A10], vitamins [A11], minerals        [A12], anabolic agents for systemic applications [A14] and        appetite stimulants [A15];    -   agents for the treatment and prevention of diseases of the blood        and the blood forming organs [B]; in particular antithrombotic        agents [B01], antihaemorrhagics [B02], antianaemic preparations        [B03] and other haematological agents [B06];    -   agents for the treatment and prevention of diseases of the        cardiovascular system [C]; in particular agents for cardiac        therapy [C01], antihypertensives [C02], diuretics [C03],        peripheral vasodilatators [C04], vasoprotectives [C05],        antihypotensives [C06A], β-adrenoceptor antagonists [C07],        calcium channel blockers [C08], agents acting on the        renin-angiotensin system [C09] and lipid reducing agents [C10];        dermatologicals [D]; in particular antifungals for systemic use        [D01B], antipsoriatics for systemic use [D05B], antiacne        preparations for systemic use [D10B];    -   agents for the treatment and prevention of diseases of the        genitourinary system and sex hormones [G]; in particular        gynaecological antiinfectives and antiseptics [G01], oxytocics        [G02A], sympathomimetic labour repressants [G02CA], prolactin        inhibitors [G02CB], hormonal contraceptives for systemic use        [G03] and urologicals [G04];    -   systemic hormone preparations excluding sex hormones and        insulins [H]; in particular pituitary and hypothalamic hormones        and analogue [H01], corticosteroids for systemic use [H02],        thyroid preparations [H03], pancreatic hormones [H04], and        agents for regulating calcium homeostatis [H05];    -   antiinfectives for systemic use [J]; in particular antibiotics        for systemic use [J01], antimycotics for systemic use [J02],        antimycobacterials [J04], antivirals for systemic use [J05],        immune sera and immunoglobulins [J06], and vaccines [J07]);    -   antineoplastic and immunomodulating agents [L] (in particular        antineoplastistic agents [L01], agents for endocrine therapy        [L02], immunostimulants [L03] and immunosuppressive agents        [L04];    -   agents for the treatment and prevention of diseases of the        musculo-skeletal system [M]; in particular antiinflammatory and        antirheumatic agents [M01], peripherally acting muscle relaxants        [M03A], directly acting muscle relaxants [M03C], antigout        preparations [M04] and agents for the treatment of bone diseases        [M05];    -   agents for the treatment and prevention of diseases of the        nervous system [N]; in particular salicylic acid the derivatives        thereof [N02BA], pyrazolones [N02BB], anilides [N02BE], ergot        alkaloids [N02CA], corticosteroid derivatives [N02CB], selective        serotonin-5HT1 agonists [N02CC], hydantoin derivatives [N03AB],        oxazolidine derivatives [N03AC], succinimide derivatives        [N03AD], carboxamide derivatives [N03AF], fatty acid derivatives        [N03AG], antiparkinson drugs [N04]), antipsychotics [N05A],        antidepressants [N06A], antidementia drugs [N06D],        parasympathomimetics [N07A] and antivertigo preparations [N07C];    -   antiparasitic products, insecticides and repellents [P]; in        particular antiprotozoals [P01], anthelmintics [P02] and        ectoparasiticides, including scabicides, insecticides and        repellents [P03];    -   agents for the treatment and prevention of diseases of the        respiratory system [R]; in particular nasal preparations [R01],        throat preparations [R02], drugs for obstructive airways        diseases [R03], expectorants, excluding combinations with cough        suppressants [R05C] and antihistamines for systemic use [R06];    -   agents for the treatment and prevention of diseases of the        sensory organs [S]; in particular otologicals [S02]; and    -   general diet products [V06] and therapeutic radiopharmaceuticals        [V10],        wherein the abbreviations stated in square brackets here (and        hereinafter) correspond to the ATC Index, as used by the WHO for        classifying pharmaceutical substances (preferred version: 2010).

In a preferred embodiment, the dosage form according to the inventioncontains one or more pharmacologically active ingredients (A) selectedfrom the group consisting of agents for cardiac therapy [C01],preferably selected from the group consisting of cardiac glycosides[C01A], antiarrhythmics, class i and iii [C01B], cardiac stimulantsexcl. cardiac glycosides [C01C], vasodilators used in cardiac diseases[C01D], and other cardiac preparations [C01E].

In another preferred embodiment, the dosage form according to theinvention contains one or more pharmacologically active ingredients (A)selected from the group consisting of antihypertensives [C002],preferably selected from the group consisting of antiadrenergic agents,centrally acting [C02A], antiadrenergic agents, ganglion-blocking[C02B], antiadrenergic agents, peripherally acting [C02C], arteriolarsmooth muscle, agents acting on [C02D], other antihypertensives [C02K],antihypertensives and diuretics in combination [C021], and combinationsof antihypertensives in atc-gr. C02 [C02N].

In still another preferred embodiment, the dosage form according to theinvention contains one or more pharmacologically active ingredients (A)selected from the group consisting of diuretics [C03], preferablyselected from the group consisting of low-ceiling diuretics, thiazides[C03A], low-ceiling diuretics, excl. thiazides [C03B], high-ceilingdiuretics [C03C], potassium-sparing agents [C03D], diuretics andpotassium-sparing agents in combination [C03E], and other diuretics[C03X].

In yet another preferred embodiment, the dosage form according to theinvention contains one or more pharmacologically active ingredients (A)selected from the group consisting of peripheral vasodilatators [C04],preferably selected from the group consisting of peripheral vasodilators[C04A].

In another preferred embodiment, the dosage form according to theinvention contains one or more pharmacologically active ingredients (A)selected from the group consisting of vasoprotectives [C05], preferablyselected from the group consisting of agents for treatment ofhemorrhoids and anal fissures for topical use [C05A], antivaricosetherapy [C05B], and capillary stabilizing agents [C05C].

In still another preferred embodiment, the dosage form according to theinvention contains one or more pharmacologically active ingredients (A)selected from the group consisting of antihypotensives [C06A].

In yet another preferred embodiment, the dosage form according to theinvention contains one or more pharmacologically active ingredients (A)selected from the group consisting of D adrenoceptor antagonists [C07],preferably selected from the group consisting of beta blocking agents[C07A], beta blocking agents and thiazides [C07B], beta blocking agentsand other diuretics [C07C], beta blocking agents, thiazides and otherdiuretics [C07D], beta blocking agents and vasodilators [C07E], and betablocking agents and other antihypertensives [C07F].

In another preferred embodiment, the dosage form according to theinvention contains one or more pharmacologically active ingredients (A)selected from the group consisting of calcium channel blockers [C08],preferably selected from the group consisting of selective calciumchannel blockers with mainly vascular effects [C08C], selective calciumchannel blockers with direct cardiac effects [C08D], non-selectivecalcium channel blockers [C08E], and calcium channel blockers anddiuretics [C08G].

In still another preferred embodiment, the dosage form according to theinvention contains one or more pharmacologically active ingredients (A)selected from the group consisting of agents acting on therenin-angiotensin system [C09], preferably selected from the groupconsisting of ACE inhibitors, plain [C09A], ACE inhibitors, combinations[C09B], angiotensin ii antagonists, plain [C09C], angiotensin iiantagonists, combinations [C09D], and other agents acting on therenin-angiotensin system [C09X].

In yet another preferred embodiment, the dosage form according to theinvention contains one or more pharmacologically active ingredients (A)selected from the group consisting of lipid reducing agents [c10],preferably selected from the group consisting of lipid modifying agents,plain [C10A], and lipid modifying agents, combinations [C10B].

In a preferred embodiment, the pharmacologically active ingredient (A)is an angiotensin converting enzyme (ACE) inhibitor, more preferably anACE-inhibitor selected from the group consisting of benazepril,captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril,moexipril, perindopril, quinapril, ramipril, spirapril, trandolapril andzofenopril.

In another preferred embodiment, the pharmacologically active ingredientis an opioid, more preferably an oxidation-sensitive opioid, mostpreferably oxymorphone or oxycodone.

According to the ATC index, opioids are divided into natural opiumalkaloids, phenylpiperidine derivatives, diphenylpropylaminederivatives, benzomorphan derivatives, oripavine derivatives, morphinanderivatives and others. Examples of natural opium alkaloids aremorphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine,diamorphine, papaveretum, and codeine. Further opioids (A) are, forexample, ethylmorphine, hydrocodone, oxymorphone, and thephysiologically acceptable derivatives thereof or compounds, preferablythe salts and solvates thereof, preferably the hydrochlorides thereof,physiologically acceptable enantiomers, stereoisomers, diastereomers andracemates and the physiologically acceptable derivatives thereof,preferably ethers, esters or amides.

Further preferred opioids includeN-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propion-amide,(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol,(1R,-2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,preferably as racemate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(6-methoxy-naphthalen-2-yl)propionate,(RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-4-chloro-2-hydroxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-5-nitro-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,1,1-(3-dimethylamino-3-phenylpentamethylen)-6-fluor-1,3,4,9-tetrahydropyrano[3,4-b]indole,in particular its hemicitrate;1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1,3,4,9-tetra-hydropyrano[3,4-b]indole,in particular its citrate; and1,1-[3-dimethylamino-3-(2-thienyl)-pentamethylen]-1,3,4,9-tetrahydropyrano[3,4-b]-6-fluoro-indole,in particular its hemicitrate, and corresponding stereoisomericcompounds, in each case the corresponding derivatives thereof,physiologically acceptable enantiomers, stereoisomers, diastereomers andracemates and the physiologically acceptable derivatives thereof, e.g.ethers, esters or amides, and in each case the physiologicallyacceptable compounds thereof, in particular the salts thereof andsolvates, e.g. hydrochlorides.

Preferred opioids are of general formula (I)

-   -   wherein    -   R₁ is —H, —OH or —OC₁₋₆-alkyl;    -   R₂ is —H or —C₁₋₆-alkyl;    -   R₃ is —H or —OH and R₄ is —H; or R₃ and R₄ together are ═O; and    -   ---- is an optional double bond;    -   or the physiologically acceptable salts thereof.

Particularly preferred opioids include oxymorphone, oxycodone,hydromorphone, and the physiologically acceptable salts thereof.

In another preferred embodiment, however, the pharmaceutical dosage formaccording to the invention does not contain any opioid, preferably anyoxidation-sensitive opioid, as defined above.

The content of the pharmacologically active ingredient (A) in thepharmaceutical dosage form is not limited.

Preferably, its content is within the range of from 0.01 to 80 wt.-%,more preferably 0.1 to 50 wt.-%, still more preferably 1 to 25 wt.-%,based on the total weight of the pharmaceutical dosage form. In apreferred embodiment, the content of pharmacologically active ingredient(A) is within the range of from 7±6 wt.-%, more preferably 7±5 wt.-%,still more preferably 5±4 wt.-%, 7±4 wt.-% or 9±4 wt.-%, most preferably5±3 wt.-%, 7±3 wt.-% or 9±3 wt.-%, and in particular 5±2 wt.-%, 7±2wt.-% or 9±2 wt.-%, based on the total weight of the pharmaceuticaldosage form. In another preferred embodiment, the content ofpharmacologically active ingredient (A) is within the range of from11±10 wt.-%, more preferably 11±9 wt.-%, still more preferably 9±6wt.-%, 11±6 wt.-%, 13±6 wt.-% or 15±6 wt.-%, most preferably 11±4 wt.-%,13±4 wt.-% or 15±4 wt.-%, and in particular 11±2 wt.-%, 13±2 wt.-% or15±2 wt.-%, based on the total weight of the pharmaceutical dosage form.In a further preferred embodiment, the content of pharmacologicallyactive ingredient (A) is within the range of from 20±6 wt.-%, morepreferably 20±5 wt.-%, still more preferably 20±4 wt.-%, most preferably20±3 wt.-%, and in particular 20±2 wt.-%, based on the total weight ofthe pharmaceutical dosage form.

Preferably, the total amount of the pharmacologically active ingredient(A) that is contained in the pharmaceutical dosage form is within therange of from 0.01 to 200 mg, more preferably 0.1 to 190 mg, still morepreferably 1.0 to 180 mg, yet more preferably 1.5 to 160 mg, mostpreferably 2.0 to 100 mg and in particular 2.5 to 80 mg.

In a preferred embodiment, the pharmacologically active ingredient (A)is contained in the pharmaceutical dosage form in an amount of 7.5±5 mg,10±5 mg, 20±5 mg, 30±5 mg, 40±5 mg, 50±5 mg, 60±5 mg, 70±5 mg, 80±5 mg,90±5 mg, 100±5 mg, 110±5 mg, 120±5 mg, 130±5, 140±5 mg, 150±5 mg, or160±5 mg. In another preferred embodiment, the pharmacologically activeingredient (A) is contained in the pharmaceutical dosage form in anamount of 5±2.5 mg, 7.5±2.5 mg, 10±2.5 mg, 15±2.5 mg, 20±2.5 mg, 25±2.5mg, 30±2.5 mg, 35±2.5 mg, 40±2.5 mg, 45±2.5 mg, 50±2.5 mg, 55±2.5 mg,60±2.5 mg, 65±2.5 mg, 70±2.5 mg, 75±2.5 mg, 80±2.5 mg, 85±2.5 mg, 90±2.5mg, 95±2.5 mg, 100±2.5 mg, 105±2.5 mg, 110±2.5 mg, 115±2.5 mg, 120±2.5mg, 125±2.5 mg, 130±2.5 mg, 135±2.5 mg, 140±2.5 mg, 145±2.5 mg, 150±2.5mg, 155±2.5 mg, or 160±2.5 mg.

In a particularly preferred embodiment, the pharmacologically activeingredient (A), preferably the opioid, is oxymorphone, preferably itsHCl salt, and the pharmaceutical dosage form is adapted foradministration twice daily. In this embodiment, the opioid (A) ispreferably contained in the pharmaceutical dosage form in an amount offrom 5 to 40 mg. In another particularly preferred embodiment,pharmacologically active ingredient (A), preferably the opioid isoxymorphone, preferably its HCl, and the pharmaceutical dosage form isadapted for administration once daily. In this embodiment,pharmacologically active ingredient (A), preferably the opioid ispreferably contained in the pharmaceutical dosage form in an amount offrom 10 to 80 mg.

In another particularly preferred embodiment, the pharmacologicallyactive ingredient (A), preferably the opioid, is oxycodone, preferablyits HCl salt, and the pharmaceutical dosage form is adapted foradministration twice daily. In this embodiment, the pharmacologicallyactive ingredient (A), preferably the opioid, is preferably contained inthe pharmaceutical dosage form in an amount of from 5 to 80 mg. Inanother particularly preferred embodiment, the pharmacologically activeingredient (A), preferably the opioid, is oxycodone, preferably its HClsalt, and the pharmaceutical dosage form is adapted for administrationonce daily. In this embodiment, the pharmacologically active ingredient(A), preferably the opioid, is preferably contained in thepharmaceutical dosage form in an amount of from 10 to 320 mg.

In still another particularly preferred embodiment, thepharmacologically active ingredient (A), preferably the opioid, ishydromorphone, preferably its HCl salt, and the pharmaceutical dosageform is adapted for administration twice daily. In this embodiment, thepharmacologically active ingredient (A), preferably the opioid, ispreferably contained in the pharmaceutical dosage form in an amount offrom 2 to 52 mg. In another particularly preferred embodiment, thepharmacologically active ingredient (A), preferably the opioid, ishydromorphone, preferably its HCl salt, and the pharmaceutical dosageform is adapted for administration once daily. In this embodiment, thepharmacologically active ingredient (A), preferably the opioid, ispreferably contained in the pharmaceutical dosage form in an amount offrom 4 to 104 mg.

The pharmaceutical dosage form according to the invention ischaracterized by excellent storage stability.

Preferably, after storage for 4 weeks at 40° C. and 75% rel. humidity,the content of the pharmacologically active ingredient (A), preferablythe opioid, amounts to at least 98.0%, more preferably at least 98.5%,still more preferably at least 99.0%, yet more preferably at least99.2%, most preferably at least 99.4% and in particular at least 99.6%,of its original content before storage. Suitable methods for measuringthe content of the pharmacologically active ingredient (A) in thepharmaceutical dosage form are known to the skilled artisan. In thisregard it is referred to the Eur. Ph. or the USP, especially to reversedphase HPLC analysis. Preferably, the pharmaceutical dosage form isstored in closed, preferably sealed containers, preferably as describedin the experimental section, most preferably being equipped with anoxygen scavenger, in particular with an oxygen scavenger that iseffective even at low relative humidity.

Preferably, after storage for 4 weeks at 40° C. and 75% rel. humidity,the content of the matrix material, preferably the polyalkylene oxide(C) amounts to at least 98.0%, more preferably at least 98.5%, stillmore preferably at least 99.0%, yet more preferably at least 99.2%, mostpreferably at least 99.4% and in particular at least 99.6%, of itsoriginal content before storage. Suitable methods for measuring thecontent of the polyalkylene oxide (C) in the pharmaceutical dosage formare known to the skilled artisan. In this regard it is referred to theEur. Ph. or the USP, especially to reversed phase HPLC analysis.

Preferably, after storage for 4 weeks at 40° C. and 75% rel. humidity,the weight average molecular weight of the polyalkylene oxide (C)amounts to at least 70%, more preferably at least 75%, still morepreferably at least 80%, yet more preferably at least 85%, mostpreferably at least 90% and in particular at least 95%, of its originalweight average molecular weight before storage.

Suitable methods for determining the weight average molecular weight ofthe polyalkylene oxide (C) in the pharmaceutical dosage form are knownto the skilled artisan. The change of the weight average molecularweight of the polyalkylene oxide (C) can for instance be evaluated byviscosity measurements after swelling of the dosage form.

It has been surprisingly found that acid (B) does not only improve thestorage stability of the dosage form but also improves theprocessability of the pharmaceutical excipients, preferably of thepolyalkylene oxide (C) upon manufacture, particularly in the course ofthermoforming such as hot-melt extrusion. There is comparativeexperimental evidence that due to the presence of acid (B) the decreaseof viscosity of polymer (C) which typically occurs upon hot-meltextrusion is substantially reduced when acid (B) is present in suitableamounts.

Preferably, the dosage form according to the invention contains acid (B)in an amount so that in the course of hot-melt extrusion of allexcipients and ingredients the gel viscosity of a homogeneous gelprepared from the dosage form amounts to at least 50%, more preferablyat least 60%, still more preferably at least 70%, yet more preferably atleast 80%, even more preferably at least 85%, most preferably at least90% and in particular at least 95% of the gel viscosity of a homogeneousgel prepared from a mixture of all excipients and ingredients of thedosage form but which has not been hot-melt extruded.

Furthermore, the dosage form according to the invention preferablycontains acid (B) in an amount so that after storage of the dosage formfor 3 months under accelerated storage conditions the gel viscosity of ahomogeneous gel prepared from the dosage form amounts to at least 50%,more preferably at least 60%, still more preferably at least 70%, yetmore preferably at least 80%, even more preferably at least 85%, mostpreferably at least 90% and in particular at least 95% of the gelviscosity of a homogeneous gel prepared from the dosage form prior tostorage. Preferably, the conditions of extrusion are defined as in theexperimental section. When preparing the homogeneous gel, the dosageform is preferably suspended in a sufficient amount of water so that atambient conditions (rotational viscosimeter) the viscosity of theresultant homogeneous gel is about 500 mPas at 40 s⁻¹ (linearity range).Once a suitable amount of water has been determined by preliminarytests, all comparative tests are then conducted under identicalconditions.

Preferably, the pharmaceutical dosage form is stored in closed,preferably sealed containers, preferably as described in theexperimental section, most preferably being equipped with an oxygenscavenger, in particular with an oxygen scavenger that is effective evenat low relative humidity.

The pharmaceutical dosage form according to the invention contains, ascomponent (B), a free physiologically acceptable acid in an amount offrom 0.001 to 5.0 wt.-%, based on the total weight of the pharmaceuticaldosage form.

The acid (B) may be organic or inorganic, liquid or solid. Solid acidsare preferred, particularly crystalline organic or inorganic acids.

Acid (B) is free. This means that the acidic functional groups of theacid (B) are not all together constituents of a salt of thepharmacologically active ingredient (A). If the pharmacologically activeingredient (A) is present as a salt of an acid, e.g. as hydrochloride,the pharmaceutical dosage form according to the invention preferablycontains as component (B) another, chemically different acid which isnot present as a constituent of the salt of the pharmacologically activeingredient (A). In other words, monoacids that form a salt withpharmacologically active ingredient (A) are not to be considered as freeacids (B) in the meaning of the present invention. When acid (B) hasmore than a single acidic functional group (e.g. phosphoric acid), theacid (B) may be present as a constituent of a salt of thepharmacologically active ingredient (A), provided that at least one ofthe acidic functional groups of the acid (B) is not involved in theformation of the salt, i.e. is free. Preferably, however, each and everyacidic functional group of acid (B) is not involved in the formation ofa salt with pharmacologically active ingredient (A). It is alsopossible, however, that free acid (B) and the acid forming a salt withpharmacologically active ingredient (A) are identical. Under thesecircumstances the acid is preferably present in molar excess compared topharmacologically active ingredient (A).

In a preferred embodiment, the acid (B) contains at least one acidicfunctional group (e.g. —CO₂H, —SO₃H, —PO₃H2, —OH and the like) having apK_(A) value within the range of 2.00±1.50, more preferably 2.00±1.25,still more preferably 2.00±1.00, yet more preferably 2.00±0.75, mostpreferably 2.00±0.50 and in particular 2.00±0.25. In another preferredembodiment, the acid contains at least one acidic functional grouphaving a pK_(A) value within the range of 2.25±1.50, more preferably2.25±1.25, still more preferably 2.25±1.00, yet more preferably2.25±0.75, most preferably 2.25±0.50 and in particular 2.25±0.25. Inanother preferred embodiment, the acid (B) contains at least one acidicfunctional group having a pK_(A) value within the range of 2.50±1.50,more preferably 2.50±1.25, still more preferably 2.50±1.00, yet morepreferably 2.50±0.75, most preferably 2.50±0.50 and in particular2.50±0.25. In another preferred embodiment, the acid (B) contains atleast one acidic functional group having a pK_(A) value within the rangeof 2.75±1.50, more preferably 2.75±1.25, still more preferably2.75±1.00, yet more preferably 2.75±0.75, most preferably 2.75±0.50 andin particular 2.75±0.25. In another preferred embodiment, the acid (B)contains at least one acidic functional group having a pK_(A) valuewithin the range of 3.00±1.50, more preferably 3.00±1.25, still morepreferably 3.00±1.00, yet more preferably 3.00±0.75, most preferably3.00±0.50 and in particular 3.00±0.25. In still another preferredembodiment, the acid (B) contains at least one acidic functional grouphaving a pK_(A) value within the range of 3.25±1.50, more preferably3.25±1.25, still more preferably 3.25±1.00, yet more preferably3.25±0.75, most preferably 3.25±0.50 and in particular 3.25±0.25.

In yet another preferred embodiment, the acid (B) contains at least oneacidic functional group having a pK_(A) value within the range of4.50±1.50, more preferably 4.50±1.25, still more preferably 4.50±1.00,yet more preferably 4.50±0.75, most preferably 4.50±0.50 and inparticular 4.50±0.25. In yet another preferred embodiment, the acid (B)contains at least one acidic functional group having a pK_(A) valuewithin the range of 4.75±1.50, more preferably 4.75±1.25, still morepreferably 4.75±1.00, yet more preferably 4.75±0.75, most preferably4.75±0.50 and in particular 4.75±0.25. In yet another preferredembodiment, the acid (B) contains at least one acidic functional grouphaving a pK_(A) value within the range of 5.00±1.50, more preferably5.00±1.25, still more preferably 5.00±1.00, yet more preferably5.00±0.75, most preferably 5.00±0.50 and in particular 5.00±0.25.

Preferably, the acid (B) is an organic carboxylic or sulfonic acid,particularly a carboxylic acid. Multicarboxylic acids and/orhydroxy-carboxylic acids are especially preferred.

In case of multicarboxylic acids, the partial salts thereof are also tobe regarded as multi-carboxylic acids, e.g. the partial sodium,potassium or ammonium salts. For example, citric acid is amulticarboxylic acid having three carboxyl groups. As long as thereremains at least one carboxyl group protonated (e.g. sodium dihydrogencitrate or disodium hydrogen citrate), the salt is to be regarded as amulticarboxylic acid. Preferably, however, all carboxyl groups of themulticarboxylic acid are protonated.

Preferably, the acid (B) is of low molecular weight, i.e., notpolymerized. Typically, the molecular weight of the acid (B) is below500 g/mol.

Examples of acids include saturated and unsaturated monocarboxylicacids, saturated and unsaturated bicarboxylic acids, tricarboxylicacids, α-hydroxyacids and β-hydroxyl-acids of monocarboxylic acids,α-hydroxyacids and β-hydroxyacids of bicarboxylic acids, α-hydroxyacidsand β-hydroxyacids of tricarboxylic acids, ketoacids, α-ketoacids,β-ketoacids, of the polycarboxylic acids, of the polyhydroxymonocarboxylic acids, of the polyhydroxy bicarboxylic acids, of thepolyhydroxy tricarboxylic acids.

Preferably, the acid (B) is selected from the group consisting ofbenzenesulfonic acid, citric acid, α-glucoheptonic acid, D-gluconicacid, glycolic acid, lactic acid, malic acid, malonic acid, mandelicacid, propanoic acid, succinic acid, tartaric acid (d, l, or dl), tosicacid (toluenesulfonic acid), valeric acid, palmitic acid, pamoic acid,sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid,glutaric acid, 4-chlorobenzenesulfonic acid, ethanedisulfonic acid,ethylsuccinic acid, fumaric acid, galactaric acid (mucic acid),D-glucuronic acid, 2-oxo-glutaric acid, glycerophosphoric acid, hippuricacid, isethionic acid (ethanolsulfonic acid), lactobionic acid, maleicacid, maleinic acid, 1,5-naphthalene-disulfonic acid,2-naphthalene-sulfonic acid, pivalic acid, terephthalic acid, thiocyanicacid, cholic acid, n-dodecyl sulfate, 3-hydroxy-2-naphthoic acid,1-hydroxy-2-naphthoic acid, oleic acid, undecylenic acid, ascorbic acid,(+)-camphoric acid, d-camphorsulfonic acid, dichloroacetic acid,ethanesulfonic acid, formic acid, methanesulfonic acid, nicotinic acid,orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharine,salicylic acid, gentisic acid, and/or 4-acetamidobenzoic acid.

The content of the acid (B) is within the range of from 0.001 to 5.0wt.-%, preferably 0.005 to 2.5 wt.-%, more preferably 0.01 to 2.0 wt.-%,still more preferably 0.05 to 1.5 wt.-%, most preferably 0.1 to 1.0wt.-% and in particular 0.2 to 0.9 wt.-%, based on the total weight ofthe pharmaceutical dosage form.

Preferably, the acid (B) is a multicarboxylic acid. More preferably, themulticarboxylic acid is selected from the group consisting of citricacid, maleic acid and fumaric acid.

Citric acid is particularly preferred.

The multicarboxylic acid, preferably citric acid, may be present in itsanhydrous form or as a solvate and hydrate, respectively, e.g., asmonohydrate.

In a preferred embodiment, the content of the acid (B), preferablycitric acid, is within the range of 0.2±0.18 wt.-%, more preferably0.2±0.15 wt.-%, still more preferably 0.2±0.12 wt.-%, yet morepreferably 0.2±0.09 wt.-%, most preferably 0.2±0.06 wt.-%, and inparticular 0.2±0.03 wt.-%, based on the total weight of thepharmaceutical dosage form.

In another preferred embodiment, the content of the acid (B), preferablycitric acid, is within the range of 0.3±0.18 wt.-%, more preferably0.3±0.15 wt.-%, still more preferably 0.3±0.12 wt.-%, yet morepreferably 0.3±0.09 wt.-%, most preferably 0.3±0.06 wt.-%, and inparticular 0.3±0.03 wt.-%, based on the total weight of thepharmaceutical dosage form.

In still another preferred embodiment, the content of the acid (B),preferably citric acid, is within the range of 0.4±0.18 wt.-%, morepreferably 0.4±0.15 wt.-%, still more preferably 0.4±0.12 wt.-%, yetmore preferably 0.4±0.09 wt.-%, most preferably 0.4±0.06 wt.-%, and inparticular 0.4±0.03 wt.-%, based on the total weight of thepharmaceutical dosage form.

In yet another preferred embodiment, the content of the acid (B),preferably citric acid, is within the range of 0.5±0.18 wt.-%, morepreferably 0.5±0.15 wt.-%, still more preferably 0.5±0.12 wt.-%, yetmore preferably 0.5±0.09 wt.-%, most preferably 0.5±0.06 wt.-%, and inparticular 0.5±0.03 wt.-%, based on the total weight of thepharmaceutical dosage form.

In yet another preferred embodiment, the content of the acid (B),preferably citric acid, is within the range of 0.6±0.18 wt.-%, morepreferably 0.6±0.15 wt.-%, still more preferably 0.6±0.12 wt.-%, yetmore preferably 0.6±0.09 wt.-%, most preferably 0.6±0.06 wt.-%, and inparticular 0.6±0.03 wt.-%, based on the total weight of thepharmaceutical dosage form.

In yet another preferred embodiment, the content of the acid (B),preferably citric acid, is within the range of 0.7±0.18 wt.-%, morepreferably 0.7±0.15 wt.-%, still more preferably 0.7±0.12 wt.-%, yetmore preferably 0.7±0.09 wt.-%, most preferably 0.7±0.06 wt.-%, and inparticular 0.7±0.03 wt.-%, based on the total weight of thepharmaceutical dosage form.

In yet another preferred embodiment, the content of the acid (B),preferably citric acid, is within the range of 0.8±0.18 wt.-%, morepreferably 0.8±0.15 wt.-%, still more preferably 0.8±0.12 wt.-%, yetmore preferably 0.8±0.09 wt.-%, most preferably 0.8±0.06 wt.-%, and inparticular 0.8±0.03 wt.-%, based on the total weight of thepharmaceutical dosage form.

In yet another preferred embodiment, the content of the acid (B),preferably citric acid, is within the range of 0.85±0.18 wt.-%, morepreferably 0.85±0.15 wt.-%, still more preferably 0.85±0.12 wt.-%, yetmore preferably 0.85±0.09 wt.-%, most preferably 0.85±0.06 wt.-%, and inparticular 0.85±0.03 wt.-%, based on the total weight of thepharmaceutical dosage form.

In still another preferred embodiment, the content of the acid (B),preferably citric acid, is within the range of 0.9±0.18 wt.-%, morepreferably 0.9±0.15 wt.-%, still more preferably 0.9±0.12 wt.-%, yetmore preferably 0.9±0.09 wt.-%, most preferably 0.9±0.06 wt.-%, and inparticular 0.9±0.03 wt.-%, based on the total weight of thepharmaceutical dosage form.

In a further preferred embodiment, the content of the acid (B),preferably citric acid, is within the range of 1.0±0.18 wt.-%, morepreferably 1.0±0.15 wt.-%, still more preferably 1.0±0.12 wt.-%, yetmore preferably 1.0±0.09 wt.-%, most preferably 1.0±0.06 wt.-%, and inparticular 1.0±0.03 wt.-%, based on the total weight of thepharmaceutical dosage form.

The pharmaceutical dosage form according to the invention comprises, ascomponent (C), a polyalkylene oxide (C) having a weight averagemolecular weight M_(w) of at least 200,000 g/mol, preferably at least500,000 g/mol, more preferably at least 750,000 g/mol, still morepreferably at least 1,000,000 g/mol, most preferably at least 2,000,000g/mol and in particular within the range of from 500,000 to 15,000,000g/mol.

Preferably, the polyalkylene oxide is selected from the group consistingof polymethylene oxide, polyethylene oxide and polypropylene oxide, thecopolymers and mixtures thereof.

Polyalkylene oxide (C) may comprise a single polyalkylene oxide having aparticular average molecular weight, or a mixture (blend) of differentpolymers, such as two, three, four or five polymers, e.g., polymers ofthe same chemical nature but different average molecular weight,polymers of different chemical nature but same average molecular weight,or polymers of different chemical nature as well as different molecularweight.

For the purpose of the specification, a polyalkylene glycol has amolecular weight of up to 20,000 g/mol whereas a polyalkylene oxide hasa molecular weight of more than 20,000 g/mol. In a preferred embodiment,the weight average over all molecular weights of all polyalkylene oxidesthat are contained in the pharmaceutical dosage form is at least 200,000g/mol. Thus, polyalkylene glycols, if any, are preferably not taken intoconsideration when determining the weight average molecular weight ofpolyalkylene oxide (C).

Preferably, the content of the polyalkylene oxide (C) is within therange of from 20 to 99 wt.-%, more preferably 25 to 95 wt.-%, still morepreferably 30 to 90 wt.-%, yet more preferably 30 to 85 wt.-%, mostpreferably 30 to 80 wt.-% and in particular 30 to 75 wt.-%, based on thetotal weight of the pharmaceutical dosage form. In a preferredembodiment, the content of the polyalkylene oxide is at least 20 wt.-%,more preferably at least 25 wt.-%, still more preferably at least 30wt.-%, yet more preferably at least 35 wt.-% and in particular at least40 wt.-%.

In a preferred embodiment, the overall content of polyalkylene oxide (C)is within the range of 25±20 wt.-%, more preferably 25±15 wt.-%, mostpreferably 25±10 wt.-%, and in particular 25±5 wt.-%. In anotherpreferred embodiment, the overall content of polyalkylene oxide (C) iswithin the range of 35±20 wt.-%, more preferably 35±15 wt.-%, mostpreferably 35±10 wt.-%, and in particular 35±5 wt.-%. In still anotherpreferred embodiment, the overall content of polyalkylene oxide (C) iswithin the range of 45±20 wt.-%, more preferably 45±15 wt.-%, mostpreferably 45±10 wt.-%, and in particular 45±5 wt.-%. In yet anotherpreferred embodiment, the overall content of polyalkylene oxide (C) iswithin the range of 55±20 wt.-%, more preferably 55±15 wt.-%, mostpreferably 55±10 wt.-%, and in particular 55±5 wt.-%. In a furtherpreferred embodiment, the overall content of polyalkylene oxide (C) iswithin the range of 65±20 wt.-%, more preferably 65±15 wt.-%, mostpreferably 65±10 wt.-%, and in particular 65±5 wt.-%. In still a furthera preferred embodiment, the overall content of polyalkylene oxide (C) iswithin the range of 75±20 wt.-%, more preferably 75±15 wt.-%, mostpreferably 75±10 wt.-%, and in particular 75±5 wt.-%. In a still furthera preferred embodiment, the overall content of polyalkylene oxide (C) iswithin the range of 80±15 wt.-%, more preferably 80±10 wt.-%, and mostpreferably 80±5 wt.-%.

In a preferred embodiment, polyalkylene oxide (C) is homogeneouslydistributed in the pharmaceutical dosage form according to theinvention. Preferably, polyalkylene oxide (C) forms a matrix in whichthe opioid (A) is embedded. In a particularly preferred embodiment, theopioid (A) and polyalkylene oxide (C) are intimately homogeneouslydistributed in the pharmaceutical dosage form so that the pharmaceuticaldosage form does not contain any segments where either opioid (A) ispresent in the absence of polyalkylene oxide (C) or where polyalkyleneoxide (C) is present in the absence of opioid (A).

When the pharmaceutical dosage form is film coated, the polyalkyleneoxide (C) is preferably homogeneously distributed in the core of thepharmaceutical dosage form, i.e. the film coating preferably does notcontain polyalkylene oxide (C). Nonetheless, the film coating as suchmay of course contain one or more polymers, which however, preferablydiffer from the polyalkylene oxide (C) contained in the core.

The polyalkylene oxide (C) may be combined with one or more differentpolymers selected from the group consisting of polyalkylene oxide,preferably polymethylene oxide, polyethylene oxide, polypropylene oxide;polyethylene, polypropylene, polyvinyl chloride, polycarbonate,polystyrene, polyvinylpyrrolidone, poly(alk)acrylate, poly(hydroxy fattyacids), such as for example poly(3-hydroxybutyrate-co-3-hydroxyvalerate)(Biopol®), poly(hydroxyvaleric acid); polycaprolactone, polyvinylalcohol, polyesteramide, polyethylene succinate, polylactone,polyglycolide, polyurethane, polyamide, polylactide, polyacetal (forexample polysaccharides optionally with modified side chains),polylactide/glycolide, polylactone, polyglycolide, polyorthoester,polyanhydride, block polymers of polyethylene glycol and polybutyleneterephthalate (Polyactive®), polyanhydride (Polifeprosan), copolymersthereof, block-copolymers thereof, and mixtures of at least two of thestated polymers, or other polymers with the above characteristics.

Preferably, the molecular weight dispersity M_(w)/M_(n) of polyalkyleneoxide (C) is within the range of 2.5±2.0, more preferably 2.5±1.5, stillmore preferably 2.5±1.0, yet more preferably 2.5±0.8, most preferably2.5±0.6, and in particular 2.5±0.4.

The polyalkylene oxide (C) (starting material) preferably has aviscosity at 25° C. of 30 to 17,600 cP, more preferably 55 to 17,600 cP,still more preferably 600 to 17,600 cP and most preferably 4,500 to17,600 cP, measured in a 5 wt.-% aqueous solution using a model RVFBrookfield viscosimeter (spindle no. 2/rotational speed 2 rpm); of 400to 4,000 cP, more preferably 400 to 800 cP or 2,000 to 4,000 cP,measured on a 2 wt.-% aqueous solution using the stated viscosimeter(spindle no. 1 or 3/rotational speed 10 rpm); or of 1,650 to 10,000 cP,more preferably 1,650 to 5,500 cP, 5,500 to 7,500 cP or 7,500 to 10,000cP, measured on a 1 wt.-% aqueous solution using the stated viscosimeter(spindle no. 2/rotational speed 2 rpm).

In a preferred embodiment according to the invention the polyalkyleneoxide (C) having a weight average molecular weight of at least 200,000g/mol is combined with at least one further polymer, preferably but notnecessarily also having a weight average molecular weight (M_(w)) of atleast 200,000 g/mol, selected from the group consisting of polyethylene,polypropylene, polyvinyl chloride, polycarbonate, polystyrene,polyacrylate, poly(hydroxy fatty acids), polycaprolactone, polyvinylalcohol, polyesteramide, polyethylene succinate, polylactone,polyglycolide, polyurethane, polyvinylpyrrolidone, polyamide,polylactide, polylactide/glycolide, polylactone, polyglycolide,polyorthoester, polyanhydride, block polymers of polyethylene glycol andpolybutylene terephthalate, polyanhydride, polyacetal, cellulose esters,cellulose ethers and copolymers thereof. Cellulose esters and celluloseethers are particularly preferred, e.g. methylcellulose, ethylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulosehydroxy-propylmethylcellulose, carboxymethylcellulose, and the like.

In a preferred embodiment, said further polymer is neither apolyalkylene oxide nor a polyalkylene glycol. Nonetheless, thepharmaceutical dosage form may contain polyalkylene glycol, e.g. asplasticizer, but then, the pharmaceutical dosage form preferably is aternary mixture of polymers:polyalkylene oxide (C)+furtherpolymer+plasticizer.

In a particularly preferred embodiment, said further polymer is ahydrophilic cellulose ester or cellulose ether, preferablyhydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) orhydroxyethylcellulose (HEC), preferably having an average viscosity(preferably measured by capillary viscosimetry or rotationalviscosimetry) of 1,000 to 150,000 mPas, more preferably 3,000 to150,000. In a preferred embodiment, the average viscosity is within therange of 110,000±50,000 mPas, more preferably 110,000±40,000 mPas, stillmore preferably 110,000±30,000 mPas, most preferably 110,000±20,000mPas, and in particular 100,000±10,000 mPas.

In a preferred embodiment the relative weight ratio of said polyalkyleneoxide (C) and said further polymer is within the range of from 20:1 to1:20, more preferably 10:1 to 1:10, still more preferably 7:1 to 1:5,yet more preferably 5:1 to 1:1, most preferably 4:1 to 1,5:1 and inparticular 3:1 to 2:1. In a preferred embodiment, the relative weightratio of said polyalkylene oxide (C) and said further polymer is withinthe range of from 10:1 to 5:1, more preferably 8:1 to 5:1, mostpreferably 7:1 to 5:1.

Preferably, the content of said further polymer amounts to 0.5 to 25wt.-%, more preferably 1.0 to 20 wt.-%, still more preferably 2.0 to22.5 wt.-%, yet more preferably 3.0 to 20 wt.-% and most preferably 4.0to 17.5 wt.-% and in particular 5.0 to 15 wt.-%, based on the totalweight of the pharmaceutical dosage form.

In a preferred embodiment, the further polymer is a cellulose ester orcellulose ether, preferably HPMC, having a content within the range of10±8 wt.-%, more preferably 10±6 wt.-%, still more preferably 10±5wt.-%, yet more preferably 10±4 wt.-%, most preferably 10±3 wt.-%, andin particular 10±2 wt.-%, based on the total weight of thepharmaceutical dosage form.

In another preferred embodiment, the further polymer is a celluloseester or cellulose ether, preferably HPMC, having a content within therange of 14±8 wt.-%, more preferably 14±6 wt.-%, still more preferably14±5 wt.-%, yet more preferably 14±4 wt.-%, most preferably 14±3 wt.-%,and in particular 14±2 wt.-%, based on the total weight of thepharmaceutical dosage form.

All polymers are preferably employed as powders. They can be soluble inwater.

Besides the pharmacologically active ingredient (A), the acid (B) andpolyalkylene oxide (C) the pharmaceutical dosage form according to theinvention may contain further constituents, such as conventionalpharmaceutical excipients.

In a preferred embodiment, the pharmaceutical dosage form comprises anantioxidant. Suitable antioxidants include ascorbic acid, α-tocopherol(vitamin E), butylhydroxyanisol, butylhydroxytoluene, salts of ascorbicacid (vitamin C), ascorbylic palmitate, monothioglycerine, coniferylbenzoate, nordihydroguajaretic acid, gallus acid esters, phosphoricacid, and the derivatives thereof, such as vitamin E-succinate orvitamin E-palmitate and/or sodium bisulphite, more preferablybutylhydroxytoluene (BHT) or butylhydroxyanisol (BHA) and/orα-tocopherol.

Preferably, the content of the antioxidant is within the range of from0.001 to 5.0 wt.-%, more preferably 0.002 to 2.5 wt.-%, more preferably0.003 to 1.5 wt.-%, still more preferably 0.005 to 1.0 wt.-%, yet morepreferably 0.01 to 0.5 wt.-%, most preferably 0.05 to 0.4 wt.-% and inparticular 0.1 to 0.3 wt.-%, based on the total weight of thepharmaceutical dosage form.

In a preferred embodiment, the content of the antioxidant is at most 5.0wt.-%, more preferably at most 4.0 wt.-%, still more preferably at most3.0 wt.-%, yet more preferably at most 2.0 wt.-%, even more preferablyat most 1.0 wt.-%, most preferably at most 0.5 wt.-% and in particularat most 0.25 wt.-%, based on the total weight of the pharmaceuticaldosage form.

A particularly preferred antioxidant is α-tocopherol. It has beensurprisingly found that α-tocopherol stabilizes polyalkylene oxide andsimultaneously destabilizes certain opioids (A), such as oxymorphone.Thus, in a preferred embodiment, the content of α-tocopherol is balancedbetween a sufficient stability of the polyalkylene oxide on the one handand a sufficient stability of the pharmacologically active ingredient(A), preferably the opioid, on the other hand.

In a preferred embodiment, the content of α-tocopherol is within therange of 0.2±0.18 wt.-%, more preferably 0.2±0.15 wt.-%, still morepreferably 0.2±0.12 wt.-%, yet more preferably 0.2±0.09 wt.-%, mostpreferably 0.2±0.06 wt.-%, and in particular 0.2±0.03 wt.-%, based onthe total weight of the pharmaceutical dosage form.

In a preferred embodiment, the relative weight ratio of the acid (B),preferably citric acid, and the antioxidant, preferably α-tocopherol, iswithin the range of from 10:1 to 1:10, more preferably 8:1 to 1:8, stillmore preferably 6:1 to 1:6, yet more preferably 5:1 to 1:4, mostpreferably 4:1 to 1:3 and in particular 3:1 to 1:2.

In another preferred embodiment, the pharmaceutical dosage form does notcomprise any of the antioxidants as defined above. Preferably, thepharmaceutical dosage form does neither contain butylhydroxytoluene(BHT), nor butylhydroxyanisol (BHA), nor α-tocopherol.

The pharmaceutical dosage form according to the invention may alsocontain a natural, semi-synthetic or synthetic wax. Waxes with asoftening point of at least 50° C., more preferably 60° C. arepreferred. Carnauba wax and beeswax are particularly preferred,especially carnauba wax.

Preferably, the release profile of the pharmacologically activeingredient (A), preferably the opioid, is matrix-retarded. Preferably,the pharmacologically active ingredient (A), preferably the opioid, isembedded in a matrix comprising the polyalkylene oxide, said matrixcontrolling the release of the pharmacologically active ingredient (A),preferably the opioid, from the pharmaceutical dosage form.

Physiologically acceptable materials which are known to the personskilled in the art may be used as supplementary matrix materials.Polymers, particularly preferably cellulose ethers, cellulose estersand/or acrylic resins are preferably used as hydrophilic matrixmaterials. Ethylcellulose, hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,poly(meth)acrylic acid and/or the derivatives thereof, such as thesalts, amides or esters thereof are very particularly preferably used asmatrix materials. Matrix materials prepared from hydrophobic materials,such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fattyalcohols or corresponding esters or ethers or mixtures thereof are alsopreferred. Mono- or diglycerides of C₁₂-C₃₀ fatty acids and/or C₁₂-C₃₀fatty alcohols and/or waxes or mixtures thereof are particularlypreferably used as hydrophobic materials. It is also possible to usemixtures of the above-stated hydrophilic and hydrophobic materials asmatrix materials.

Preferably, the relative weight ratio of the polyalkylene oxide to thepharmacologically active ingredient (A), preferably the opioid, is atleast 0.5:1, more preferably at least 1:1, at least 2:1, at least 3:1,at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1 orat least 9:1; still more preferably at least 10:1 or at least 15:1, yetmore preferably at least 20:1, most preferably at least 30:1 and inparticular at least 40:1. In a preferred embodiment, the relative weightratio of the polyalkylene oxide to the pharmacologically activeingredient (A), preferably the opioid, is within the range of from 3:1to 50:1, more preferably 3:1 to 40:1 and in particular 3:1 to 30:1.

The pharmaceutical dosage form according to the invention preferablycontains a plasticizer. The plasticizer improves the processability ofthe polyalkylene oxide. A preferred plasticizer is polyalkylene glycol,like polyethylene glycol, triacetin, fatty acids, fatty acid esters,waxes and/or microcrystalline waxes. Particularly preferred plasticizersare polyethylene glycols, such as PEG 6000.

Preferably, the content of the plasticizer is within the range of from0.1 to 25 wt.-%, more preferably 0.5 to 22.5 wt.-%, still morepreferably 1.0 to 20 wt.-%, yet more preferably 2.5 to 17.5 wt.-%, mostpreferably 5.0 to 15 wt.-% and in particular 7.5 to 12.5 wt.-%, based onthe total weight of the pharmaceutical dosage form.

In a preferred embodiment, the plasticizer is a polyalkylene glycolhaving a content within the range of 10±8 wt.-%, more preferably 10±6wt.-%, still more preferably 10±5 wt.-%, yet more preferably 10±4 wt.-%,most preferably 10±3 wt.-%, and in particular 10±2 wt.-%, based on thetotal weight of the pharmaceutical dosage form.

In another preferred embodiment, the plasticizer is a polyalkyleneglycol having a content within the range of 15±8 wt.-%, more preferably15±6 wt.-%, still more preferably 15±5 wt.-%, yet more preferably 15±4wt.-%, most preferably 15±3 wt.-%, and in particular 15±2 wt.-%, basedon the total weight of the pharmaceutical dosage form.

In a preferred embodiment, the relative weight ratio of the polyalkyleneoxide to the polyalkylene glycol is within the range of 4.2±2:1, morepreferably 4.2±1.5:1, still more preferably 4.2±1:1, yet more preferably4.2±0.5:1, most preferably 4.2±0.2:1, and in particular 4.2±0.1:1. Thisratio satisfies the requirements of relative high polyalkylene oxidecontent and good extrudability.

When manufacturing the dosage forms from slices that are obtained bycutting the extrudate strand, the weight of the slices determines theweight of the resulting dosage form. Pronounced variation in weight ofthese slices results in an accordant weight deviation of dosage formsfrom the target weight. The weight variation of slices depends stronglyon the surface properties of the extrudate strand. A strand with athoroughly smooth surface allows the generation of slices exhibiting alow weight variation. In contrast, a wavy or shark skinning strandresults in slices exhibiting a higher weight variation therebyincreasing the number of rejects.

It has now been surprisingly found that the surface properties of theextrudate strand can be triggered by the polyalkylene oxide:polyalkyleneglycol weight ratio.

Preferred compositions X₁ to X₃₂ of the pharmaceutical dosage formaccording to the invention are summarized in the tables here below:

wt.-% X₁ X₂ X₃ X₄ pharmacologically active ingredient (A) 1.50 ± 1.251.50 ± 1.00 1.50 ± 0.75 1.50 ± 0.50  (e.g. oxymorphone HCl) acid (B)(e.g. citric acid)  0.5 ± 0.30  0.5 ± 0.25  0.5 ± 0.20  0.5 ± 0.15polyalkylene oxide (C) 77 ± 22 77 ± 20 77 ± 15 77 ± 10  cellulose esteror ether (e.g. HPMC) 12 ± 10  12 ± 7.5 12 ± 5  12 ± 2.5 plasticizer(e.g. PEG)  10 ± 7.5 10 ± 5   10 ± 2.5 10 ± 1.0 antioxidant (e.g.α-tocopherol)  0.2 ± 0.12 0.2 ± 0.1  0.2 ± 0.05  0.2 ± 0.03

wt.-% X₅ X₆ X₇ X₈ pharmacologically active ingredient (A) 2.33 ± 1.252.33 ± 1.00 2.33 ± 0.75 2.33 ± 0.50 (e.g. oxymorphone HCl) acid (B)(e.g. citric acid) 0.85 ± 0.60 0.85 ± 0.50 0.85 ± 0.25 0.85 ± 0.15polyalkylene oxide (C) 70 ± 25 70 ± 20 70 ± 15 70 ± 10 cellulose esteror ether (e.g. HPMC)  10 ± 9.5  10 ± 7.5 10 ± 5   10 ± 2.5 plasticizer(e.g. PEG) 16.6 ± 7.5  16.6 ± 5   16.6 ± 2.5  16.6 ± 1.0  antioxidant(e.g. α-tocopherol)  0.2 ± 0.12 0.2 ± 0.1  0.2 ± 0.05  0.2 ± 0.03

wt.-% X₉ X₁₀ X₁₁ X₁₂ pharmacologically active ingredient (A) 3.50 ± 1.253.50 ± 1.00 3.50 ± 0.75 3.50 ± 0.50 (e.g. oxymorphone HCl) acid (B)(e.g. citric acid) 0.85 ± 0.60 0.85 ± 0.50 0.85 ± 0.25 0.85 ± 0.15polyalkylene oxide (C) 69 ± 30 69 ± 20 69 ± 15 69 ± 10 cellulose esteror ether (e.g. HPMC)  10 ± 9.5  10 ± 7.5 10 ± 5   10 ± 2.5 plasticizer(e.g. PEG) 16.4 ± 7.5  16.4 ± 5   16.4 ± 2.5  16.4 ± 1.0  antioxidant(e.g. α-tocopherol)  0.2 ± 0.12 0.2 ± 0.1  0.2 ± 0.05  0.2 ± 0.03

wt.-% X₁₃ X₁₄ X₁₅ X₁₆ pharmacologically active ingredient (A) 4.65 ±1.25 4.65 ± 1.00 4.65 ± 0.75 4.65 ± 0.50 (e.g. oxymorphone HCl) acid (B)(e.g. citric acid) 0.85 ± 0.60 0.85 ± 0.50 0.85 ± 0.25 0.85 ± 0.15polyalkylene oxide (C) 68 ± 30 68 ± 20 68 ± 15 68 ± 10 cellulose esteror ether (e.g. HPMC)  10 ± 9.5  10 ± 7.5 10 ± 5   10 ± 2.5 plasticizer(e.g. PEG) 16.2 ± 7.5  16.2 ± 5   16.2 ± 2.5  16.2 ± 1.0  antioxidant(e.g. α-tocopherol)  0.2 ± 0.12 0.2 ± 0.1  0.2 ± 0.05  0.2 ± 0.03

wt.-% X₁₇ X₁₈ X₁₉ X₂₀ pharmacologically active ingredient (A) 6.98 ±1.25 6.98 ± 1.00 6.98 ± 0.75 6.98 ± 0.50 (e.g. oxymorphone HCl) acid (B)(e.g. citric acid) 0.85 ± 0.60 0.85 ± 0.50 0.85 ± 0.25 0.85 ± 0.15polyalkylene oxide (C) 66 ± 30 66 ± 20 66 ± 15 66 ± 10 cellulose esteror ether (e.g. HPMC)  10 ± 9.5  10 ± 7.5 10 ± 5   10 ± 2.5 plasticizer(e.g. PEG) 15.8 ± 7.5  15.8 ± 5   15.8 ± 2.5  15.8 ± 1.0  antioxidant(e.g. α-tocopherol)  0.2 ± 0.12 0.2 ± 0.1  0.2 ± 0.05  0.2 ± 0.03

wt.-% X₂₁ X₂₂ X₂₃ X₂₄ pharmacologically active ingredient (A) 9.30 ±1.25 9.30 ± 1.00 9.30 ± 0.75 9.30 ± 0.50 (e.g. oxymorphone HCl) acid (B)(e.g. citric acid) 0.85 ± 0.60 0.85 ± 0.50 0.85 ± 0.25 0.85 ± 0.15polyalkylene oxide (C) 64 ± 30 64 ± 20 64 ± 15 64 ± 10 cellulose esteror ether (e.g. HPMC)  10 ± 9.5  10 ± 7.5 10 ± 5   10 ± 2.5 plasticizer(e.g. PEG) 15.3 ± 7.5  15.3 ± 5   15.3 ± 2.5  15.3 ± 1.0  antioxidant(e.g. α-tocopherol)  0.2 ± 0.12 0.2 ± 0.1  0.2 ± 0.05  0.2 ± 0.03

wt.-% X₂₅ X₂₆ X₂₇ X₂₈ pharmacologically active ingredient (A) 13.95 ±1.25  13.95 ± 1.00  13.95 ± 0.75 13.95 ± 0.50  (e.g. oxymorphone HCl)acid (B) (e.g. citric acid) 0.85 ± 0.60 0.85 ± 0.50  0.85 ± 0.25 0.85 ±0.15 polyalkylene oxide (C) 60 ± 30 60 ± 20  60 ± 15 60 ± 10 celluloseester or ether (e.g. HPMC)  10 ± 9.5  10 ± 7.5 10 ± 5  10 ± 2.5plasticizer (e.g. PEG) 13.9 ± 7.5  13.9 ± 5   13.9 ± 2.5 13.9 ± 1.0 antioxidant (e.g. α-tocopherol)  0.2 ± 0.12 0.2 ± 0.1  0.2 ± 0.05  0.2 ±0.03

wt.-% X₂₉ X₃₀ X₃₁ X₃₂ pharmacologically active ingredient (A) 18.60 ±1.25  18.60 ± 1.00  18.60 ± 0.75 18.60 ± 0.50  (e.g. oxymorphone HCl)acid (B) (e.g. citric acid) 0.85 ± 0.60 0.85 ± 0.50  0.85 ± 0.25 0.85 ±0.15 polyalkylene oxide (C) 57 ± 30 57 ± 20  57 ± 15 57 ± 10 celluloseester or ether (e.g. HPMC)  10 ± 9.5  10 ± 7.5 10 ± 5  10 ± 2.5plasticizer (e.g. PEG) 13.6 ± 7.5  13.6 ± 5   13.6 ± 2.5 13.6 ± 1.0 antioxidant (e.g. α-tocopherol)  0.2 ± 0.12 0.2 ± 0.1  0.2 ± 0.05  0.2 ±0.03

In a preferred embodiment, the pharmaceutical dosage form has a totalweight within the range of 100±75 mg, more preferably 100±50 mg, mostpreferably 100±25 mg. In another preferred embodiment, thepharmaceutical dosage form has a total weight within the range of 200±75mg, more preferably 200±50 mg, most preferably 200±25 mg. In anotherpreferred embodiment, the pharmaceutical dosage form has a total weightwithin the range of 250±75 mg, more preferably 250±50 mg, mostpreferably 250±25 mg. In still another preferred embodiment, thepharmaceutical dosage form has a total weight within the range of 300±75mg, more preferably 300±50 mg, most preferably 300±25 mg. In yet anotherpreferred embodiment, the pharmaceutical dosage form has a total weightwithin the range of 400±75 mg, more preferably 400±50 mg, mostpreferably 400±25 mg.

In a preferred embodiment, the pharmaceutical dosage form has a totalweight within the range of 500±250 mg, more preferably 500±200 mg, mostpreferably 500±150 mg. In another preferred embodiment, thepharmaceutical dosage form has a total weight within the range of750±250 mg, more preferably 750±200 mg, most preferably 750±150 mg. Inanother preferred embodiment, the pharmaceutical dosage form has a totalweight within the range of 1000±250 mg, more preferably 1000±200 mg,most preferably 1000±150 mg. In still another preferred embodiment, thepharmaceutical dosage form has a total weight within the range of1250±250 mg, more preferably 1250±200 mg, most preferably 1250±150 mg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention has an overall density within the range of 1.19±0.30g/cm³, more preferably 1.19±0.25 g/cm³, still more preferably 1.19±0.20g/cm³, yet more preferably 1.19±0.15 g/cm³, most preferably 1.19±0.10g/cm³, and in particular 1.19±0.05 g/cm³. Preferably, the overalldensity of the pharmaceutical dosage form according to the invention iswithin the range of 1.17±0.02 g/cm³, 1.19±0.02 or 1.21±0.02. Methods formeasuring the density of a dosage form are known to a person skilled inthe art. The overall density of a dosage form can for example bedetermined by means of the mercury porosimetry method or the heliumpycnometer method, as described in Ph. Eur.

Preferably, the pharmaceutical dosage form according to the invention isadapted for oral administration. It is also possible, however, toadminister the pharmaceutical dosage form via different routes and thus,the pharmaceutical dosage form may alternatively be adapted for buccal,lingual, rectal or vaginal administration. Implants are also possible.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is adapted for administration once daily. In anotherpreferred embodiment, the pharmaceutical dosage form according to theinvention is adapted for administration twice daily. In still anotherpreferred embodiment, the pharmaceutical dosage form according to theinvention is adapted for administration thrice daily.

For the purpose of the specification, “twice daily” means equal ornearly equal time intervals, i.e., about every 12 hours, or differenttime intervals, e.g., 8 and 16 hours or 10 and 14 hours, between theindividual administrations.

For the purpose of the specification, “thrice daily” means equal ornearly equal time intervals, i.e., about every 8 hours, or differenttime intervals, e.g., 6, 6 and 12 hours; or 7, 7 and 10 hours, betweenthe individual administrations.

Preferably, the pharmaceutical dosage form according to the inventioncauses an at least partially delayed or prolonged release of thepharmacologically active ingredient (A), preferably opioid (A).

Controlled or prolonged release is understood according to the inventionpreferably to mean a release profile in which the pharmacologicallyactive ingredient (A), preferably the opioid, is released over arelatively long period with reduced intake frequency with the purpose ofextended therapeutic action. Preferably, the meaning of the term“prolonged release” is in accordance with the European guideline on thenomenclature of the release profile of pharmaceutical dosage forms(CHMP). This is achieved in particular with peroral administration. Theexpression “at least partially delayed or prolonged release” coversaccording to the invention any pharmaceutical dosage forms which ensuremodified release of the pharmacologically active ingredients (A),preferably the opioids, contained therein. The pharmaceutical dosageforms preferably comprise coated or uncoated pharmaceutical dosageforms, which are produced with specific auxiliary substances, byparticular processes or by a combination of the two possible options inorder purposefully to change the release rate or location of release.

In the case of the pharmaceutical dosage forms according to theinvention, the release time profile of a controlled release form may bemodified e.g. as follows: extended release, repeat action release,prolonged release and sustained release.

For the purpose of the specification “controlled release” preferablymeans a product in which the release of active compound over time iscontrolled by the type and composition of the formulation. For thepurpose of the specification “extended release” preferably means aproduct in which the release of active compound is delayed for a finitelag time, after which release is unhindered. For the purpose of thespecification “repeat action release” preferably means a product inwhich a first portion of active compound is released initially, followedby at least one further portion of active compound being releasedsubsequently. For the purpose of the specification “prolonged release”preferably means a product in which the rate of release of activecompound from the formulation after administration has been reduced overtime, in order to maintain therapeutic activity, to reduce toxiceffects, or for some other therapeutic purpose. For the purpose of thespecification “sustained release” preferably means a way of formulatinga medicine so that it is released into the body steadily, over a longperiod of time, thus reducing the dosing frequency. For further details,reference may be made, for example, to K. H. Bauer, Lehrbuch derPharmazeutischen Technologie, 6th edition, WVG Stuttgart, 1999; and Eur.Ph.

The pharmaceutical dosage form according to the invention may compriseone or more pharmacologically active ingredients (A), preferablyopioids, at least in part in a further controlled release form, whereincontrolled release may be achieved with the assistance of conventionalmaterials and processes known to the person skilled in the art, forexample by embedding the substance in a controlled release matrix or byapplying one or more controlled release coatings. Substance releasemust, however, be controlled such that addition of delayed-releasematerials does not impair the necessary breaking strength. Controlledrelease from the pharmaceutical dosage form according to the inventionis preferably achieved by embedding the substance in a matrix.Preferably, polyalkylene oxide (C) serves as such a matrix. Theauxiliary substances acting as matrix materials control release. Matrixmaterials may, for example, be hydrophilic, gel-forming materials, fromwhich release proceeds mainly by diffusion, or hydrophobic materials,from which release proceeds mainly by diffusion from the pores in thematrix.

Preferably, the release profile is substantially matrix controlled,preferably by embedding pharmacologically active ingredient (A),preferably opioid (A), in a matrix comprising polyalkylene oxide (C) andoptionally, further matrix materials. Preferably, the release profile isnot osmotically driven. Preferably, release kinetics is not zero order.

Preferably, under physiological conditions the pharmaceutical dosageform according to the invention has released after 30 minutes 0.1 to75%, after 240 minutes 0.5 to 95%, after 480 minutes 1.0 to 100% andafter 720 minutes 2.5 to 100% of the pharmacologically active ingredient(A), preferably opioid (A). Further preferred release profiles R₁ to R₆are summarized in the table here below [all data in wt.-% of releasedpharmacologically active ingredient (A), preferably opioid (A)]:

time R₁ R₂ R₃ R₄ R₅ R₆  60 min 0-30 0-50 0-50 15-25 20-30 20-50 120 min0-40 0-75 0-75 25-40 35-50 40-75 240 min 3-55 3-95 10-95  40-70 55-7560-95 480 min 10-65  10-100 35-100 60-90 80-95  80-100 720 min 20-75 20-100 55-100  70-100  90-100  90-100 960 min 30-88  30-100 70-100 >80 95-100 1440 min  50-100 50-100 >90 2160 min  >80 >80

Further preferred release profiles R₁ to R₆ are summarized in the tablehere below [all data in wt.-% of released pharmacologically activeingredient (A), preferably opioid (A)]:

time R₇ R₈ R₉ R₁₀ R₁₁ R₁₂  30 min 17.5 ± 7.5 17.5 ± 6.5 17.5 ± 5.5 17.5± 4.5 17.5 ± 3.5 17.5 ± 2.5  60 min 27.0 ± 8.0 27.0 ± 7.0 27.0 ± 6.027.0 ± 5.0 27.0 ± 4.0 27.0 ± 3.0 120 min 41.5 ± 9.5 41.5 ± 8.5 41.5 ±7.5 41.5 ± 6.5 41.5 ± 5.5 41.5 ± 4.5 240 min  64.5 ± 12.5  64.5 ± 11.5 64.5 ± 10.5 64.5 ± 9.5 64.5 ± 8.5 64.5 ± 7.5 480 min  88.0 ± 12.0  88.0± 11.0  88.0 ± 10.0 88.0 ± 9.0 88.0 ± 8.0 88.0 ± 7.0 720 min 96.0 ± 9.096.0 ± 8.0 96.0 ± 7.0 96.0 ± 6.0 96.0 ± 5.0 96.0 ± 4.0 840 min 97.5 ±7.5 97.5 ± 6.5 97.5 ± 5.5 97.5 ± 4.5 97.5 ± 3.5 97.5 ± 2.5

Preferably, the release profile of the pharmaceutical dosage formaccording to the present invention is stable upon storage, preferablyupon storage at elevated temperature, e.g. 37° C., for 3 months insealed containers. In this regard “stable” means that when comparing theinitial release profile with the release profile after storage, at anygiven time point the release profiles deviate from one another by notmore than 20%, more preferably not more than 15%, still more preferablynot more than 10%, yet more preferably not more than 7.5%, mostpreferably not more than 5.0% and in particular not more than 2.5%.

Preferably, under in vitro conditions the pharmaceutical dosage form hasreleased after 0.5 h 1.0 to 35 wt.-%, after 1 h 5.0 to 45 wt.-%, after 2h 10 to 60 wt.-%, after 4 h at least 15 wt.-%, after 6 h at least 20wt.-%, after 8 h at least 25 wt.-% and after 12 h at least 30 wt.-% ofthe pharmacologically active ingredient (A), preferably the opioid, thatwas originally contained in the pharmaceutical dosage form.

Suitable in vitro conditions are known to the skilled artisan. In thisregard it can be referred to, e.g., the Eur. Ph. Preferably, the releaseprofile is measured under the following conditions: Paddle apparatusequipped with sinker, 50 rpm, 37±5° C., 900 mL simulated intestinalfluid pH 6.8 (phosphate buffer) or pH 4.5. In a preferred embodiment, torotational speed of the paddle is increased to 100 rpm.

In a preferred embodiment, after preferably oral administration of thepharmaceutical dosage form according to the invention, in vivo theaverage peak plasma level (C_(max)) is on average reached after t_(max)4.0±2.5 h, more preferably after t_(max) 4.0±2.0 h, still morepreferably after t_(max) 4.0±1.5 h, most preferably after t_(max)4.0±1.0 h and in particular after t_(max) 4.0±0.5 h. In anotherpreferred embodiment, after preferably oral administration of thepharmaceutical dosage form according to the invention, in vivo theaverage peak plasma level (C_(max)) is on average reached after t_(max)5.0±2.5 h, more preferably after t_(max)5.0±2.0 h, still more preferablyafter t_(max) 5.0±1.5 h, most preferably after t_(max) 5.0±1.0 h and inparticular after t_(max) 5.0±0.5 h. In still another preferredembodiment, after preferably oral administration of the pharmaceuticaldosage form according to the invention, in vivo the average peak plasmalevel (C_(max)) is on average reached after t_(max)6.0±2.5 h, morepreferably after t_(max) 6.0±2.0 h, still more preferably after t_(max)6.0±1.5 h, most preferably after t_(max) 6.0±1.0 h and in particularafter t_(max) 6.0±0.5 h.

In a preferred embodiment, the average value for t_(1/2) afterpreferably oral administration of the pharmaceutical dosage formaccording to the invention in vivo is 4.0±2.5 h, more preferably 4.0±2.0h, still more preferably 4.0±1.5 h, most preferably 4.0±1.0 h, and inparticular 4.0±0.5 h. In another preferred embodiment, the average valuefor t_(1/2) after preferably oral administration of the pharmaceuticaldosage form according to the invention in vivo is preferably 5.0±2.5 h,more preferably 5.0±2.0 h, still more preferably 5.0±1.5 h, mostpreferably 5.0±1.0 h, and in particular 5.0±0.5 h. In still anotherpreferred embodiment, the average value for t_(1/2) after preferablyoral administration of the pharmaceutical dosage form according to theinvention in vivo is preferably 6.0±2.5 h, more preferably 6.0±2.0 h,still more preferably 6.0±1.5 h, most preferably 6.0±1.0 h, and inparticular 6.0±0.5 h.

Preferably, the pharmaceutical dosage form according to the inventioncontains a coating, preferably a film-coating. Suitable coatingmaterials are known to the skilled person. Suitable coating materialsare commercially available, e.g. under the trademarks Opadry® andEudragit®.

Examples of suitable materials include cellulose esters and celluloseethers, such as methylcellulose (MC), hydroxypropylmethylcellulose(HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC),sodium carboxymethylcellulose (Na-CMC), ethylcellulose (EC), celluloseacetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP);poly(meth)acrylates, such as aminoalkylmethacrylate copolymers,ethylacrylate methylmethacrylate copolymers, methacrylic acidmethylmethacrylate copolymers, methacrylic acid methylmethacrylatecopolymers; vinyl polymers, such as polyvinylpyrrolidone,polyvinylacetatephthalate, polyvinyl alcohol, polyvinylacetate; andnatural film formers, such as shellack.

In a particularly preferred embodiment, the coating is water-soluble. Ina preferred embodiment, the coating is based on polyvinyl alcohol, suchas polyvinyl alcohol-part. hydrolyzed, and may additionally containpolyethylene glycol, such as macrogol 3350, and/or pigments. In anotherpreferred embodiment, the coating is based onhydroxypropylmethylcellulose, preferably hypromellose type 2910 having aviscosity of 3 to 15 mPas.

The coating of the pharmaceutical dosage form can increase its storagestability.

The coating can be resistant to gastric juices and dissolve as afunction of the pH value of the release environment. By means of thiscoating, it is possible to ensure that the pharmaceutical dosage formaccording to the invention passes through the stomach undissolved andthe active compound is only released in the intestines. The coatingwhich is resistant to gastric juices preferably dissolves at a pH valueof between 5 and 7.5. Corresponding materials and methods for thedelayed release of active compounds and for the application of coatingswhich are resistant to gastric juices are known to the person skilled inthe art, for example from “Coated Pharmaceutical dosageforms—Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects,Test Methods and Raw Materials” by Kurt H. Bauer, K. Lehmann, Hermann P.Osterwald, Rothgang, Gerhart, 1st edition, 1998, Medpharm ScientificPublishers.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains no substances which irritate the nasal passagesand/or pharynx, i.e. substances which, when administered via the nasalpassages and/or pharynx, bring about a physical reaction which is eitherso unpleasant for the patient that he/she does not wish to or cannotcontinue administration, for example burning, or physiologicallycounteracts taking of the corresponding active compound, for example dueto increased nasal secretion or sneezing. Further examples of substanceswhich irritate the nasal passages and/or pharynx are those which causeburning, itching, urge to sneeze, increased formation of secretions or acombination of at least two of these stimuli. Corresponding substancesand the quantities thereof which are conventionally to be used are knownto the person skilled in the art. Some of the substances which irritatethe nasal passages and/or pharynx are accordingly based on one or moreconstituents or one or more plant parts of a hot substance drug.Corresponding hot substance drugs are known per se to the person skilledin the art and are described, for example, in “PharmazeutischeBiologie—Drogen und ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner,2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982,pages 82 et seq. The corresponding description is hereby introduced as areference and is deemed to be part of the disclosure.

The pharmaceutical dosage form according to the invention furthermorepreferably contains no antagonists for the pharmacologically activeingredient (A), preferably no opioid antagonists more preferably noantagonists against psychotropic substances, in particular noantagonists against opioids (A). Antagonists suitable for a givenpharmacologically active ingredient (A) are known to the person skilledin the art and may be present as such or in the form of correspondingderivatives, in particular esters or ethers, or in each case in the formof corresponding physiologically acceptable compounds, in particular inthe form of the salts or solvates thereof. The pharmaceutical dosageform according to the invention preferably contains no antagonistsselected from among the group comprising naloxone, naltrexone,nalmefene, nalide, nalmexone, nalorphine or naluphine, in each caseoptionally in the form of a corresponding physiologically acceptablecompound, in particular in the form of a base, a salt or solvate; and noneuroleptics, for example a compound selected from among the groupcomprising haloperidol, promethacine, fluphenazine, perphenazine,levomepromazine, thioridazine, perazine, chlorpromazine,chlorprothixine, zuclopenthixol, flupentixol, prothipendyl, zotepine,benperidol, pipamperone, melperone and bromperidol.

The pharmaceutical dosage form according to the invention furthermorepreferably contains no emetic. Emetics are known to the person skilledin the art and may be present as such or in the form of correspondingderivatives, in particular esters or ethers, or in each case in the formof corresponding physiologically acceptable compounds, in particular inthe form of the salts or solvates thereof. The pharmaceutical dosageform according to the invention preferably contains no emetic based onone or more constituents of ipecacuanha (ipecac) root, for example basedon the constituent emetine, as are, for example, described in“Pharmazeutische Biologie—Drogen und ihre Inhaltsstoffe” by Prof. Dr.Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag,Stuttgart, N.Y., 1982. The corresponding literature description ishereby introduced as a reference and is deemed to be part of thedisclosure. The pharmaceutical dosage form according to the inventionpreferably also contains no apomorphine as an emetic.

Finally, the pharmaceutical dosage form according to the inventionpreferably also contains no bitter substance. Bitter substances and thequantities effective for use may be found in US-2003/0064099 A1, thecorresponding disclosure of which should be deemed to be the disclosureof the present application and is hereby introduced as a reference.Examples of bitter substances are aromatic oils, such as peppermint oil,eucalyptus oil, bitter almond oil, menthol, fruit aroma substances,aroma substances from lemons, oranges, limes, grapefruit or mixturesthereof, and/or denatonium benzoate.

The pharmaceutical dosage form according to the invention accordinglypreferably contains neither substances which irritate the nasal passagesand/or pharynx, nor antagonists for the pharmacologically activeingredient (A), preferably the opioid (A), nor emetics, nor bittersubstances.

The pharmaceutical dosage form according to the invention is preferablyadapted for oral administration.

Typically, the pharmaceutical dosage form according to the inventionassumes the form of a tablet. Preferably, the pharmaceutical dosage formis neither in film form, nor multi-particulate.

The pharmaceutical dosage form according to the invention is preferablytamper-resistant. Preferably, tamper-resistance is achieved based on themechanical properties of the pharmaceutical dosage form so thatcomminution is avoided or at least substantially impeded. According tothe invention, the term comminution means the pulverization of thepharmaceutical dosage form using conventional means usually available toan abuser, for example a pestle and mortar, a hammer, a mallet or otherconventional means for pulverizing under the action of force. Thus,tamper-resistance preferably means that pulverization of thepharmaceutical dosage form using conventional means is avoided or atleast substantially impeded.

Preferably, the mechanical properties of the pharmaceutical dosage formaccording to the invention, particularly its breaking strength,substantially rely on the presence and spatial distribution ofpolyalkylene oxide (C), although its mere presence does typically notsuffice in order to achieve said properties. The advantageous mechanicalproperties of the pharmaceutical dosage form according to the inventionmay not automatically be achieved by simply processing pharmacologicallyactive ingredient (A), acid (B), polyalkylene oxide (C), and optionallyfurther excipients by means of conventional methods for the preparationof pharmaceutical dosage forms. In fact, usually suitable apparatusesmust be selected for the preparation and critical processing parametersmust be adjusted, particularly pressure/force, temperature and time.Thus, even if conventional apparatuses are used, the process protocolsusually must be adapted in order to meet the required criteria.

The pharmaceutical dosage form according to the invention has a breakingstrength of at least 300 N, preferably at least 400 N, more preferablyat least 500 N, still more preferably at least 750 N, yet morepreferably at least 1000 N, most preferably at least 1250 N and inparticular at least 1500 N.

The “breaking strength” (resistance to crushing) of a pharmaceuticaldosage form is known to the skilled person. In this regard it can bereferred to, e.g., W. A. Ritschel, Die Tablette, 2. Auflage, EditionCantor Verlag Aulendorf, 2002; H Liebermann et al., Pharmaceuticaldosage forms: Tablets, Vol. 2, Informa Healthcare; 2 edition, 1990; andEncyclopedia of Pharmaceutical Technology, Informa Healthcare; 1edition.

For the purpose of the specification, the breaking strength ispreferably defined as the amount of force that is necessary in order tofracture the pharmaceutical dosage form (=breaking force). Therefore,for the purpose of the specification the pharmaceutical dosage form doespreferably not exhibit the desired breaking strength when it breaks,i.e., is fractured into at least two independent parts that areseparated from one another. In another preferred embodiment, however,the pharmaceutical dosage form is regarded as being broken if the forcedecreases by 25% (threshold value) of the highest force measured duringthe measurement (see below).

The pharmaceutical dosage forms according to the invention aredistinguished from conventional pharmaceutical dosage forms in that, dueto their breaking strength, they cannot be pulverized by the applicationof force with conventional means, such as for example a pestle andmortar, a hammer, a mallet or other usual means for pulverization, inparticular devices developed for this purpose (tablet crushers). In thisregard “pulverization” means crumbling into small particles that wouldimmediately release the pharmacologically active compound (A),preferably the opioid, in a suitable medium. Avoidance of pulverizationvirtually rules out oral or parenteral, in particular intravenous ornasal abuse.

Conventional tablets typically have a breaking strength well below 200 Nin any direction of extension. The breaking strength of conventionalround tablets may be estimated according to the following empiricalformula: Breaking Strength [in N]=10×Diameter Of The Tablet [in mm].Thus, according to said empirical formula, a round tablet having abreaking strength of at least 300 N would require a diameter of at least30 mm). Such a tablet, however, could not be swallowed. The aboveempirical formula preferably does not apply to the pharmaceutical dosageforms of the invention, which are not conventional but rather special.

Further, the actual mean chewing force is about 220 N (cf., e.g., P. A.Proeschel et al., J Dent Res, 2002, 81(7), 464-468). This means thatconventional tablets having a breaking strength well below 200 N may becrushed upon spontaneous chewing, whereas the pharmaceutical dosageforms according to the invention may not.

Still further, when applying a gravitational acceleration of about 9.81m/s², 300 N correspond to a gravitational force of more than 30 kg, i.e.the pharmaceutical dosage forms according to the invention canpreferably withstand a weight of more than 30 kg without beingpulverised.

Methods for measuring the breaking strength of a pharmaceutical dosageform are known to the skilled artisan. Suitable devices are commerciallyavailable.

For example, the breaking strength (resistance to crushing) can bemeasured in accordance with the Eur. Ph. 5.0, 2.9.8 or 6.0, 2.09.08“Resistance to Crushing of Tablets”. The test is intended to determine,under defined conditions, the resistance to crushing of tablets,measured by the force needed to disrupt them by crushing. The apparatusconsists of 2 jaws facing each other, one of which moves towards theother. The flat surfaces of the jaws are perpendicular to the directionof movement. The crushing surfaces of the jaws are flat and larger thanthe zone of contact with the tablet. The apparatus is calibrated using asystem with a precision of 1 Newton. The tablet is placed between thejaws, taking into account, where applicable, the shape, the break-markand the inscription; for each measurement the tablet is oriented in thesame way with respect to the direction of application of the force (andthe direction of extension in which the breaking strength is to bemeasured). The measurement is carried out on 10 tablets, taking carethat all fragments of tablets have been removed before eachdetermination. The result is expressed as the mean, minimum and maximumvalues of the forces measured, all expressed in Newton.

A similar description of the breaking strength (breaking force) can befound in the USP. The breaking strength can alternatively be measured inaccordance with the method described therein where it is stated that thebreaking strength is the force required to cause a tablet to fail (i.e.,break) in a specific plane. The tablets are generally placed between twoplatens, one of which moves to apply sufficient force to the tablet tocause fracture. For conventional, round (circular cross-section)tablets, loading occurs across their diameter (sometimes referred to asdiametral loading), and fracture occurs in the plane. The breaking forceof tablets is commonly called hardness in the pharmaceutical literature;however, the use of this term is misleading. In material science, theterm hardness refers to the resistance of a surface to penetration orindentation by a small probe. The term crushing strength is alsofrequently used to describe the resistance of tablets to the applicationof a compressive load. Although this term describes the true nature ofthe test more accurately than does hardness, it implies that tablets areactually crushed during the test, which is often not the case.

Alternatively, the breaking strength (resistance to crushing) can bemeasured in accordance with WO 2005/016313, WO 2005/016314, and WO2006/082099, which can be regarded as a modification of the methoddescribed in the Eur. Ph. The apparatus used for the measurement ispreferably a “Zwick Z 2.5” materials tester, F_(max)=2.5 kN with amaximum draw of 1150 mm, which should be set up with one column and onespindle, a clearance behind of 100 mm and a test speed adjustablebetween 0.1 and 800 mm/min together with testControl software.Measurement is performed using a pressure piston with screw-in insertsand a cylinder (diameter 10 mm), a force transducer, F_(max). 1 kN,diameter=8 mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, withmanufacturer's test certificate M according to DIN 55350-18 (Zwick grossforce F_(max)=1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Ulm,Germany) with Order No BTC-FR 2.5 TH. D09 for the tester, Order NoBTC-LC 0050N. P01 for the force transducer, Order No BO 70000 S06 forthe centring device.

In a preferred embodiment of the invention, the breaking strength ismeasured by means of a breaking strength tester e.g. Sotax®, type HT100or type HT1 (Allschwil, Switzerland). Both, the Sotax® HT100 and theSotax® HT1 can measure the breaking strength according to two differentmeasurement principles: constant speed (where the test jaw is moved at aconstant speed adjustable from 5-200 mm/min) or constant force (wherethe test jaw increases force linearly adjustable from 5-100 N/sec). Inprinciple, both measurement principles are suitable for measuring thebreaking strength of the pharmaceutical dosage form according to theinvention. Preferably, the breaking strength is measured at constantspeed, preferably at a constant speed of 120 mm/min.

In a preferred embodiment, the pharmaceutical dosage form is regarded asbeing broken if it is fractured into at least two separate pieces.

The pharmaceutical dosage form according to the invention preferablyexhibits mechanical strength over a wide temperature range, in additionto the breaking strength (resistance to crushing) optionally alsosufficient hardness, impact resistance, impact elasticity, tensilestrength and/or modulus of elasticity, optionally also at lowtemperatures (e.g. below −24° C., below −40° C. or in liquid nitrogen),for it to be virtually impossible to pulverize by spontaneous chewing,grinding in a mortar, pounding, etc. Thus, preferably, the comparativelyhigh breaking strength of the pharmaceutical dosage form according tothe invention is maintained even at low or very low temperatures, e.g.,when the pharmaceutical dosage form is initially chilled to increase itsbrittleness, for example to temperatures below −25° C., below −40° C. oreven in liquid nitrogen.

The pharmaceutical dosage form according to the invention ischaracterized by a certain degree of breaking strength. This does notmean that the pharmaceutical dosage form must also exhibit a certaindegree of hardness. Hardness and breaking strength are differentphysical properties. Therefore, the tamper resistance of thepharmaceutical dosage form does not necessarily depend on the hardnessof the pharmaceutical dosage form. For instance, due to its breakingstrength, impact strength, elasticity modulus and tensile strength,respectively, the pharmaceutical dosage form can preferably be deformed,e.g. plastically, when exerting an external force, for example using ahammer, but cannot be pulverized, i.e., crumbled into a high number offragments. In other words, the pharmaceutical dosage form according tothe invention is characterized by a certain degree of breaking strength,but not necessarily also by a certain degree of form stability.

Therefore, in the meaning of the specification, a pharmaceutical dosageform that is deformed when being exposed to a force in a particulardirection of extension but that does not break (plastic deformation orplastic flow) is preferably to be regarded as having the desiredbreaking strength in said direction of extension.

A particularly preferred embodiment of the invention relates to atamper-resistant pharmaceutical dosage form having a breaking strengthof at least 300 N and being thermoformed by hot-melt extrusion, saidpharmaceutical dosage form comprising

-   -   a pharmacologically active ingredient (A), preferably an opioid,        particularly preferred an opioid selected from the group        consisting of oxymorphone, oxycodone, hydromorphone, and the        physiologically acceptable salts thereof;    -   a free physiologically acceptable multicarboxylic acid (B),        preferably citric acid, wherein the content of the acid (B) is        within the range of from 0.001 to 5.0 wt.-%, based on the total        weight of the pharmaceutical dosage form;    -   an antioxidant, wherein the content of the antioxidant,        preferably α-tocopherol, is within the range of from 0.001 to        5.0 wt.-%, based on the total weight of the pharmaceutical        dosage form; and    -   a polyalkylene oxide (C) having a weight average molecular        weight M_(w) of at least 200,000 g/mol;        wherein    -   the pharmacologically active ingredient (A) is embedded in a        matrix comprising the polyalkylene oxide (C), said matrix        controlling the release of the pharmacologically active        ingredient (A) from the pharmaceutical dosage form; and    -   after storage for 4 weeks at 40° C. and 75% rel. humidity, the        content of pharmacologically active ingredient (A), preferably        opioid (A), amounts to at least 98.0% of its original content        before storage.

The pharmaceutical dosage form according to the invention may beproduced by different processes, the particularly preferred of which areexplained in greater detail below. Several suitable processes havealready been described in the prior art. In this regard it can bereferred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO2006/082097, and WO 2006/082099.

The present invention also relates to pharmaceutical dosage forms thatare obtainable by any of the processes described here below.

In general, the process for the production of the pharmaceutical dosageform according to the invention preferably comprises the followingsteps:

-   (a) mixing all ingredients;-   (b) optionally pre-forming the mixture obtained from step (a),    preferably by applying heat and/or force to the mixture obtained    from step (a), the quantity of heat supplied preferably not being    sufficient to heat the polyalkylene oxide (C) up to its softening    point;-   (c) hardening the mixture by applying heat and force, it being    possible to supply the heat during and/or before the application of    force and the quantity of heat supplied being sufficient to heat the    polyalkylene oxide (C) at least up to its softening point;-   (d) optionally singulating the hardened mixture;-   (e) optionally shaping the pharmaceutical dosage form; and-   (f) optionally providing a film coating.

Heat may be supplied directly, e.g. by contact or by means of hot gassuch as hot air, or with the assistance of ultrasound. Force may beapplied and/or the pharmaceutical dosage form may be shaped for exampleby direct tabletting or with the assistance of a suitable extruder,particularly by means of a screw extruder equipped with two screws(twin-screw-extruder) or by means of a planetary gear extruder.

The final shape of the pharmaceutical dosage form may either be providedduring the hardening of the mixture by applying heat and force (step(c)) or in a subsequent step (step (e)). In both cases, the mixture ofall components is preferably in the plastified state, i.e. preferably,shaping is performed at a temperature at least above the softening pointof the polyalkylene oxide (C). However, extrusion at lower temperatures,e.g. ambient temperature, is also possible and may be preferred.

Shaping can be performed, e.g., by means of a tabletting presscomprising die and punches of appropriate shape.

A particularly preferred process for the manufacture of thepharmaceutical dosage form of the invention involves hot-melt extrusion.In this process, the pharmaceutical dosage form according to theinvention is produced by thermoforming with the assistance of anextruder, preferably without there being any observable consequentdiscoloration of the extrudate. It has been surprisingly found that acid(B) is capable of suppressing discoloration. In the absence of acid (B),the extrudate tends to develop beige to yellowish coloring whereas inthe presence of acid (B) the extrudates are substantially colorless,i.e. white.

This process is characterized in that

-   -   a) all components are mixed,    -   b) the resultant mixture is heated in the extruder at least up        to the softening point of the polyalkylene oxide (C) and        extruded through the outlet orifice of the extruder by        application of force,    -   c) the still plastic extrudate is singulated and formed into the        pharmaceutical dosage form or    -   d) the cooled and optionally reheated singulated extrudate is        formed into the pharmaceutical dosage form.

Mixing of the components according to process step a) may also proceedin the extruder.

The components may also be mixed in a mixer known to the person skilledin the art. The mixer may, for example, be a roll mixer, shaking mixer,shear mixer or compulsory mixer.

Before blending with the remaining components, polyalkylene oxide (C) ispreferably provided according to the invention with an antioxidant,preferably α-tocopherol. This may proceed by mixing the two components,the polyalkylene oxide (C) and the antioxidant, preferably by dissolvingor suspending the antioxidant in a highly volatile solvent andhomogeneously mixing this solution or suspension with polyalkylene oxide(C) and removing the solvent by drying, preferably under an inert gasatmosphere.

The, preferably molten, mixture which has been heated in the extruder atleast up to the softening point of polyalkylene oxide (C) is extrudedfrom the extruder through a die with at least one bore.

The process according to the invention requires the use of suitableextruders, preferably screw extruders. Screw extruders which areequipped with two screws (twin-screw-extruders) are particularlypreferred.

The extrusion is preferably performed so that the expansion of thestrand due to extrusion is not more than 30%, i.e. that when using a diewith a bore having a diameter of e.g. 6 mm, the extruded strand shouldhave a diameter of not more than 8 mm. More preferably, the expansion ofthe strand is not more than 25%, still more preferably not more than20%, most preferably not more than 15% and in particular not more than10%.

Preferably, extrusion is performed in the absence of water, i.e., nowater is added. However, traces of water (e.g., caused by atmospherichumidity) may be present.

The extruder preferably comprises at least two temperature zones, withheating of the mixture at least up to the softening point of thepolyalkylene oxide (C) proceeding in the first zone, which is downstreamfrom a feed zone and optionally mixing zone. The throughput of themixture is preferably from 1.0 kg to 15 kg/hour. In a preferredembodiment, the throughput is from 1 to 3.5 kg/hour. In anotherpreferred embodiment, the throughput is from 4 to 15 kg/hour.

In a preferred embodiment, the die head pressure is within the range offrom 25 to 100 bar. The die head pressure can be adjusted inter alia bydie geometry, temperature profile and extrusion speed.

The die geometry or the geometry of the bores is freely selectable. Thedie or the bores may accordingly exhibit a round, oblong or ovalcross-section, wherein the round cross-section preferably has a diameterof 0.1 mm to 15 mm and the oblong cross-section preferably has a maximumlengthwise extension of 21 mm and a crosswise extension of 10 mm.Preferably, the die or the bores have a round cross-section. The casingof the extruder used according to the invention may be heated or cooled.The corresponding temperature control, i.e. heating or cooling, is soarranged that the mixture to be extruded exhibits at least an averagetemperature (product temperature) corresponding to the softeningtemperature of the polyalkylene oxide (C) and does not rise above atemperature at which the pharmacologically active ingredient (A),preferably the opioid, to be processed may be damaged. Preferably, thetemperature of the mixture to be extruded is adjusted to below 180° C.,preferably below 150° C., but at least to the softening temperature ofpolyalkylene oxide (C). Typical extrusion temperatures are 120° C. and130° C.

In a preferred embodiment, the extruder torque is within the range offrom 30 to 95%. Extruder torque can be adjusted inter alia by diegeometry, temperature profile and extrusion speed.

After extrusion of the molten mixture and optional cooling of theextruded strand or extruded strands, the extrudates are preferablysingulated. This singulation may preferably be performed by cutting upthe extrudates by means of revolving or rotating knives, water jetcutters, wires, blades or with the assistance of laser cutters.

Preferably, intermediate or final storage of the optionally singulatedextrudate or the final shape of the pharmaceutical dosage form accordingto the invention is performed under oxygen-free atmosphere which may beachieved, e.g., by means of oxygen-scavengers.

The singulated extrudate may be press-formed into tablets in order toimpart the final shape to the pharmaceutical dosage form.

The application of force in the extruder onto the at least plasticizedmixture is adjusted by controlling the rotational speed of the conveyingdevice in the extruder and the geometry thereof and by dimensioning theoutlet orifice in such a manner that the pressure necessary forextruding the plasticized mixture is built up in the extruder,preferably immediately prior to extrusion. The extrusion parameterswhich, for each particular composition, are necessary to give rise to apharmaceutical dosage form with desired mechanical properties, may beestablished by simple preliminary testing.

For example but not limiting, extrusion may be performed by means of atwin-screw-extruder type ZSE 18 or ZSE 27 (Leistritz, Nuirnberg,Germany), screw diameters of 18 or 27 mm. Screws having eccentric endsmay be used. A heatable die with a round bore having a diameter of 7, 8,or 9 mm may be used. The extrusion parameters may be adjusted e.g. tothe following values: rotational speed of the screws: 120 Upm; deliveryrate2 kg/h for a ZSE 18 or 8 kg/h for a ZSE 27; product temperature: infront of die 125° C. and behind die 135° C.; and jacket temperature:110° C.

Preferably, extrusion is performed by means of twin-screw-extruders orplanetary-gear-extruders, twin-screw extruders (co-rotating orcontra-rotating) being particularly preferred.

The pharmaceutical dosage form according to the invention is preferablyproduced by thermoforming with the assistance of an extruder without anyobservable consequent discoloration of the extrudates.

The process for the preparation of the pharmaceutical dosage formaccording to the invention is preferably performed continuously.Preferably, the process involves the extrusion of a homogeneous mixtureof all components. It is particularly advantageous if the thus obtainedintermediate, e.g. the strand obtained by extrusion, exhibits uniformproperties. Particularly desirable are uniform density, uniformdistribution of the active compound, uniform mechanical properties,uniform porosity, uniform appearance of the surface, etc. Only underthese circumstances the uniformity of the pharmacological properties,such as the stability of the release profile, may be ensured and theamount of rejects can be kept low.

A further aspect of the invention relates to a packaging containing apharmaceutical dosage form according to the invention and an oxygenscavenger. Suitable packages include blister packages and bottles, suchas glass bottles or bottles made from thermoplastic polymers.

Suitable oxygen scavengers are known to the skilled artisan. The oxygenscavenger can be any scavenger known in the art to scavenge oxygen. Bothorganic and inorganic oxygen scavengers can be used.

In one embodiment, the oxygen scavenger is any metal complex exhibitingoxygen scavenging activity. Examples include complexes containing one ormore of aluminum, aluminum ferrosilicon, antimony, beryllium, calciumsilicon, cerium, cobalt, gallium, hafnium, iron, magnesium alloy, nickelcatalyst, selenium, silicon, silver, strontium, titanium, zinc, and/orzirconium.

In yet another embodiment, one or more elements from Group IA of theperiodic table and their alloys and compounds may be used as oxygenscavengers. Examples of Group IA elements include cesium, lithium,potassium, sodium. Further examples of inorganic oxygen scavengersinclude one or more of sodium azide (NaN₃), sodium sulfite (Na₂SO₃),hydrazine, and hydroxylamine.

In one embodiment, the oxygen scavenger is an organic compound. Examplesinclude one or more of the polyterpenes, ascorbic acid, aminopolycarboxylic acid, cyclohexanedione, tetramethyl piperidone, andheterocyclic compounds with N-substituted amino groups.

Oxygen scavengers and the application thereof in pharmaceuticalpackaging are known to the skilled artisan. In a preferred embodiment,the oxygen scavenger is selected from the group consisting ofmetal-catalyzed oxidizable organic polymers and anti-oxidants.Particularly preferred are those oxygen scavengers that are able toperform in a dry environment of below 60% relative humidity, preferablybelow 30% relative humidity and that are combined with a dessicant.Examples of commercially available oxygen scavengers satisfying theserequirements include Pharmakeep® KD10 and KD20.

It has been surprisingly found that the storage stability of thepharmaceutical dosage form can be increased when keeping the oxygencontent of the atmosphere within the packaging low. Methods forpackaging pharmaceutical dosage forms and the application of suitableoxygen scavengers are known to the skilled artisan. In this regard itcan be referred to e.g. D. A. Dean, Pharmaceutical Packaging Technology,Taylor & Francis, 1st ed.; F. A. Paine et al., Packaging Pharmaceuticaland Healthcare Products, Springer, 1st ed.; and O. G. Piringer et al.,Plastic Packaging: Interactions with Food and Pharmaceuticals,Wiley-VCH, 2nd ed.

As far as the packaging is concerned, round bottles made frompolyolefins, preferably from HDPE, are preferred. The thickness of thebottle wall is preferably at least 0.25 mm, more preferably at least 0.5mm, otherwise the bottle may collapse.

As far as the lid of the packaging is concerned, the packaging ispreferably induction or heat-sealed with an aluminium foil.

It has been surprisingly found that by selecting an appropriate shape ofthe packaging and sealing, the vacuum that is produced by the effect ofthe oxygen scavenger (underpressure of about 20,000 Pa=2 N/cm²) can behandled without causing a collapse of the packaging. Induction sealing(e.g. 3 seconds energy) is preferred. When sealing a 75 ml bottle havingan opening with a diameter of 1 inch with aluminium foil, anunderpressure of 20,000 Pa due to oxygen scavenging results in a forceof about 10 N corresponding to the force that is exerted by a weight of1 kg.

The mechanical stability of the sealing can be tested either byintroducing an appropriate amount of oxygen scavenger in the bottle,sealing it and waiting for a sufficient period of time, e.g. 2 days, sothat the oxygen is scavenged and an underpressure of about 20,000 Pa hasbeen developed. Alternatively, the bottle may be sealed without anyoxygen scavenger in its interior and a weight of 1 kg can be placed onthe aluminium foil externally thus, simulating the force.

A further aspect of the invention relates to the use of apharmacologically active ingredient (A), preferably an opioid, for themanufacture of the pharmaceutical dosage form as described above for thetreatment of pain.

A further aspect of the invention relates to the use of a pharmaceuticaldosage form as described above for avoiding or hindering the abuse ofthe pharmacologically active ingredient (A), preferably the opioid,contained therein.

A further aspect of the invention relates to the use of a pharmaceuticaldosage form as described above for avoiding or hindering theunintentional overdose of the opioid (A) contained therein.

In this regard, the invention also relates to the use of apharmacologically active ingredient (A), preferably an opioid, asdescribed above and/or a polyalkylene oxide (C) as described above forthe manufacture of the pharmaceutical dosage form according to theinvention for the prophylaxis and/or the treatment of a disorder,thereby preventing an overdose of the pharmacologically activeingredient (A), preferably the opioid, particularly due to comminutionof the pharmaceutical dosage form by mechanical action.

Further, the invention relates to a method for the prophylaxis and/orthe treatment of a disorder comprising the administration of thepharmaceutical dosage form according to the invention, therebypreventing an overdose of the pharmacologically active ingredient (A),preferably the opioid, particularly due to comminution of thepharmaceutical dosage form by mechanical action. Preferably, themechanical action is selected from the group consisting of chewing,grinding in a mortar, pounding, and using apparatuses for pulverizingconventional pharmaceutical dosage forms.

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

EXAMPLE 1

Tablets were prepared by hot-melt extrusion of various homogeneousconstituent mixtures under the following, identical extrusionconditions:

-   -   extruder type: Leistritz Extruder ZSE18PH 40D equipped with high        shear screws and a die of 9 mm diameter    -   throughput: 1.0 kg/h    -   revolution velocity: 100 rpm    -   barrel temperature: 100° C.    -   extrudate temperature: 120° C.

The extrudate was cut into slices of 325 mg containing about 5 mgoxymorphone hydrochloride.

The individual constituents of the extruded mixtures as well as thetotal amount of decomposition products before and after storage underaccelerated storage conditions are summarized in the table here below:

constituents (wt.-%) decomposition products (wt.-%) ex. (A) PEO PEG HPMCα-toc. further ingredient (wt.-%) oNo¹ oNo² Σ¹ Σ² A₁ 1.5 76.9 10.0 10.01.5 / 0.06 0.58 0.41 1.93 A₂ 1.5 77.5 10.0 10.0 1.0 / 0.09 0.49 0.581.81 A₃ 1.5 78.0 10.0 10.0 0.5 / 0.08 0.36 0.56 1.64 A₄ 1.5 78.3 10.010.0 0.2 / 0.08 0.26 0.63 1.51 A₅ 1.5 78.5 10.0 10.0 0.0 / 0.07 0.170.81 1.69 B₁ 1.5 76.9 10.0 10.0 1.5 / 0.06 0.58 0.41 1.93 B₂ 1.5 40.010.0 46.9 1.5 / 0.09 0.55 0.64 1.76 B₃ 1.5 50.0 10.0 36.9 1.5 / 0.000.52 0.29 1.64 B₄ 1.5 50.0 36.9 10.0 1.5 / 0.11 0.76 0.36 1.74 C₁ 1.576.9 10.0 10.0 1.5 / 0.06 0.58 0.41 1.93 C₂ 1.5 76.9 / 10.0 1.5 10.00Lutrol ® F68 0.05 0.53 0.65 1.83 C₃ 1.5 50.0 10.0 10.0 1.5 26.90mannitol 0.08 0.82 0.39 2.72 C₄ 1.5 76.9 / 10.0 1.5 10.00 carnaubawax0.12 0.53 0.39 1.03 D₁ 1.5 76.9 10.0 10.0 1.5 / 0.06 0.58 0.41 1.93 D₂1.5 76.8 10.0 10.0 1.5 0.10 fumaric acid 0.05 0.48 0.52 1.70 D₃ 1.5 76.810.0 10.0 1.5 0.10 Na-EDTA 0.07 0.51 0.48 1.77 D₄ 1.5 76.8 10.0 10.0 1.50.10 citric acid 0.07 0.48 0.37 1.45 E₁ 1.5 76.9 10.0 10.0 1.5 / 0.060.58 0.41 1.93 E₂ 1.5 76.8 10.0 10.0 1.5 0.10 citric acid 0.07 0.48 0.371.45 E₃ 1.5 76.7 10.0 10.0 1.5 0.20 citric acid 0.00 0.40 0.20 1.13 E₄1.5 76.4 10.0 10.0 1.5 0.50 citric acid 0.00 0.06 0.12 0.17 (A):oxymorphone hydrochloride PEO: polyethylene oxide M_(w) 7 mio g/mol PEG:polyethylene glycol 6000 HPMC: hypromellose 100,000 Pa*s α-toc.:α-tocopherol oNo: oxymorphone-N-oxide (mixture) Σ: sum of all impurities¹after extrusion, before storage ²after storage, amber glass bottles,plastic cap, 4 weeks, 40° C., 75% rel. humidity

The decomposition products were analyzed by HPLC-UV. The elution peakfor oxymorphone-N-oxide could not be sufficiently base-line separatedfrom a peak of an unknown degradation product (called “UK 0.83”). Thus,both peaks were jointly integrated. It becomes evident from a comparisonof examples A₁ to A₅ that the content of oxymorphone-N-oxide beforestorage (oNo¹) is not substantially changed when the content ofantioxidant α-tocopherol is decreased from 1.5 wt.-% to 1.0 wt.-%, 0.5wt.-%, 0.2 wt.-% and even 0 wt.-%. Upon storage (oNo²), however, thecontent of oxymorphone-N-oxide is proportional to the content ofα-tocopherol. This is most surprising because oxymorphone-N-oxide is anoxidation product and one would expect that antioxidants usually rathersuppress than support the formation of oxidation products.

Nonetheless, the complete omission of antioxidant (α-tocopherol) canhave disadvantages. It could be shown by viscosity measurements (in theabsence of acid (B)) that the high molecular polyethylene oxide isdegraded upon extrusion and/or storage in the absence of antioxidant.However, it has now been surprisingly found that to a certain extent theacid (B) in turn can compensate such degradation so that in certainembodiments antioxidants can be omitted or the content thereof can besubstantially decreased.

It has been surprisingly found that about 0.2 wt.-% α-tocopherol sufficein order to stabilize the polyethylene oxide; higher contents ofα-tocopherol do not result in higher viscosities of the polyalkyleneoxide and, thus, do not prevent PEO more pronounced from degradation.Thus, the content of antioxidant (α-tocopherol) is preferably balancedso that on the one side, the high molecular weight polyethylene oxide issufficiently stabilized and that on the other side, the undesiredformation of oxymorphone-N-oxide is kept low during storage.

Further, it becomes evident from a comparison of examples B₁ to B₄ andexamples C₁ to C₄ that the partial replacement of the high molecularweight polyethylene oxide or the total replacement of the polyethyleneglycol by an alternative plasticizer does not result in a substantialdecrease of the content of undesired oxymorphone-N-oxide. This issurprising because one would expect that polyethylene oxide andpolyethylene glycol are potential peroxide carriers and that a reductionthereof would result in a reduction of oxidative processes such as theoxidation of oxymorphone to oxymorphone-N-oxide.

Still further, it becomes evident from a comparison of examples D₁ to D₅and E₁ to E₄ that the addition of physiologically acceptable acids,particularly citric acid, leads to a reduction of the formation ofoxymorphone-N-oxide. This effect is more pronounced when the amount ofacid is increased. At a concentration of 0.1 wt.-%, the effect iscomparatively weak, but at a concentration of 0.2 wt.-% the effect isstronger and is further enhanced when the concentration of citric acidis increased. Not only the amount of oxymorphone-N-oxide is decreased,but also the total amount of decomposition products, particularly ofthose having high HPLC retention times.

EXAMPLE 2

Tablets that had been manufactured in analogy to ex. A₁, B₁, C₁, D₁ andE₁ above were packaged in different packaging materials and stored at40° C. and 75% rel. humidity. The decomposition products before andafter storage under accelerated storage conditions are summarized in thetable here below:

closed HDPE, closed amber sealed with open amber glass + oxygen closedamber closed amber aluminium foil glass scavenger glass + desiccantglass + argon before 4 8 4 8 4 8 4 8 4 8 storage weeks weeks weeks weeksweeks weeks weeks weeks weeks weeks 323.64 324.05 325.57 323.56 337.25325.23 322.65 321.27 322.69 324.62 324.30 mg mg mg mg mg mg mg mg mg mgmg content oxymorphone 96.30% 92.90% 89.40% 93.70% 88.50% 96.70% 94.80%94.60% 92.50% 94.60% 92.50% purity oxymorphone 99.18% 97.70% 96.70%98.03% 94.50% 99.10% 98.62% 98.59% 97.98% 98.36% 98.04% contentα-tocopherol 91.69% 91.51% 90.89% 93.51% 79.94% 94.52% 93.62% 90.56%88.23% 93.51% 92.18% oxymorphone-N-oxide 0.09% 0.64% 1.16% 0.19% 0.53%0.03% 0.04% 0.15% 0.24% 0.17% 0.30% UK 0.83 0.00% 0.00% 0.00% 0.36%2.15% 0.06% 0.08% 0.32% 0.77% 0.00% 0.00% Sum of oxymorphone-N- 0.09%0.64% 1.16% 0.55% 2.63% 0.09% 0.12% 0.37% 1.01% 0.17% 0.30% oxide and UK0.83 main unknown 0.13% 0.38% 0.43% 0.45% 2.15% 0.16% 0.18% 0.32% 0.77%0.46% 0.34% Sum of impurities Σ 0.73% 2.22% 3.21% 1.88% 5.44% 0.82%0.95% 1.33% 1.94% 1.55% 1.88% HDPE bottles had a volume of 75 ml. Theoxygen scavenger was Pharmakeep ® KD20 (Mitsubishi, Japan).

It has been surprisingly found that inclusion of an oxygen scavenger inthe packaging results in a further stabilization of the dosage form sothat the formation of decomposition products is limited to extremely lowvalues.

EXAMPLE 3

Tablets were manufactured as described in example 1, packed into HDPEbottles of 75 ml volume together with an oxygen scavenger combined witha desiccant (Pharmakeep 20 KD), closed with a plastic cap with inductionseal.

The individual constituents of the extruded mixtures, the total amountof decomposition products before and after storage under acceleratedstorage conditions are summarized in the table here below:

constituents (wt.-%) decomposition products (wt.-%) ex. (A) PEO PEG HPMCα-toc. Citric acid oNo¹ oNo² oNo³ Σ¹ Σ² Σ³ F₁ 1.5 73.8 10.0 14.0 0.2 0.5nd nd nd nd nd 0.05 F₂ 1.5 77.8 10.0 10.0 0.2 0.5 nd nd nd nd 0.05 0.10(A): oxymorphone hydrochloride PEO: polyethylene oxide M_(w) 7 mio g/molPEG: polyethylene glycol 6000 HPMC: hypromellose 100,000 Pa*s α-toc.:α-tocopherol oNo: oxymorphone-N-oxide (mixture) Σ: sum of all impurities¹after extrusion, before storage ²after storage, HDPE bottles, plasticcap with induction seal, oxygen scavenger, 4 weeks, 40° C., 75% rel.humidity ³after storage, HDPE bottles, plastic cap with induction seal,oxygen scavenger, 8 weeks, 40° C., 75% rel. humidity

The results reveal that the purity of the product is very high aftermanufacturing and that the product exhibit stable during 8 weeks storageunder accelerated conditions of 40° C./75% rel. humidity.

EXAMPLE 4

Tablets were manufactured as described in example 1 but cut into slicesof 215 mg representing 5 mg or 40 mg of oxymorphone HCl, after formingthe tablets were coated with about 6.5 mg each of a conventional OpadryII film-coat containing polyvinylalcohol as the film forming excipient,packed into HDPE bottles of 75 ml volume together with an oxygenscavenger combined with a desiccant (Pharmakeep 20 KD), closed with aplastic cap with induction seal.

The individual constituents of the extruded mixtures, the total amountof decomposition products before and after storage under acceleratedstorage conditions are summarized in the table here below:

constituents (wt.-%) decomposition products (wt.-%) ex. (A) PEO PEG HPMCα-toc. Citric acid oNo¹ oNo² Σ¹ Σ² G₁ 2.33 70.0 16.63 10.0 0.2 0.84 ndnd nd nd G₂ 18.6 56.8 13.56 10.0 0.2 0.84 nd nd 0.05 0.05 (A):oxymorphone hydrochloride PEO: polyethylene oxide M_(w) 7 mio g/mol PEG:polyethylene glycol 6000 HPMC: hypromellose 100,000 Pa*s α-toc.:α-tocopherol oNo: oxymorphone-N-oxide (mixture) Σ: sum of all impurities¹after extrusion, before storage ²after storage, HDPE bottles, plasticcap with induction seal, oxygen scavenger, 1 month, 40° C., 75% rel.humidity

EXAMPLE 5

The most preferred dosage form according to example 3 is also suitablefor the stabilization of oxycodone. This could be demonstrated for aformulation containing 80 mg of oxycodone HCl manufactured analogue toexample 1 but, the extrudate was cut into slices of 400 mg:

constituents (wt.-%) decomposition products (wt.-%) ex. (A) PEO PEG HPMCα-toc. Citric acid oNo¹ oNo² Σ¹ Σ² H₁ 20 54.3 15 10 0.2 0.5 0.06 0.070.22 0.13 (A): oxycodone PEO: polyethylene oxide M_(w) 7 mio g/mol PEG:polyethylene glycol 6000 HPMC: hypromellose 100,000 Pa*s α-toc.:α-tocopherol oNo: oxycodone-N-oxide (Impurity D + E) ¹after extrusion,before storage ²after storage, amber glass bottles, plastic cap, oxygenscavenger with desiccant (Pharmakeep 20KD) 1 month, 40° C., 75% rel.humidity

EXAMPLE 6

In a single dose (40 mg oxymorphone HCl, tablets of example 4),randomized, three-way crossover study with 1 week between treatmentssubjects were fasted overnight and meals were served 4 and 10 hoursafter dosing. No water was given within ±1 hour of dosing. All tabletswere taken with 240 mL of water (example T).

PK samples were taken for oxymorphone and 6-OH-oxymorphone predose andup through 48 hours after dosing.

Bioequivalence was compared to Opana ER® (reference R).

The results are summarized in the tables here below:

Treatment Mean SD CV C_(max) [pg/mL] T 2147 989 46% R 2671 1163 44% AUCT[pg*h/mL] T 38695 13836 36% R 38171 14652 38% AUC [pg*h/mL] T 4257515836 37% R 41296 15242 37%

Point Lower Limit Upper Limit Estimate T/R 90% CI 90% CI C_(max) 79.3771.69 87.87 AUCT 101.98 95.17 109.29 AUC 102.24 95.48 109.48 CI =confidence interval

It becomes evident that the dosage forms according to the inventionhaving an increased breaking strength are bioequivalent to conventionaldosage forms (Opana ER®).

EXAMPLE 7

Tablets were prepared under identical conditions by hot-melt extrusionof two homogeneous constituent mixtures I₁ and I₂:

I₁ I₂ Oxymorphone HCl [%] 11.1 11.1 PEO [%] 68.2 63.2 PEG [%] 10.0 15.0HPMC Shin Etsu [%] 10.0 10.0 α-tocopherol [%] 0.2 0.2 Citric acid,anhydrous [%] 0.5 0.5 Tablet weight [mg] 360 360 PEO:PEG 6.82:1 4.21:1under the following, identical extrusion conditions:

-   -   extruder type: Leistritz Extruder type Micro 27 GL 40 D equipped        with medium shear screws and a die of 8 mm diameter    -   throughput: 10 kg/h    -   revolution velocity: 120 rpm    -   manufacturing time: 30 min    -   temperature of hottest heating zone: 100° C.    -   die temperature: 130° C.

The extrudate was cut into slices of 360 mg containing about 40 mgoxymorphone hydrochloride.

100 slices were weighed individually and the standard deviation ofweight was calculated. Slices of composition 11 (PEO:PEG=6.82:1) showeda standard deviation of 2.3%, whereas slices of composition I₂(PEO:PEG=4.21:1) showed a standard deviation of 1.6% only.

It becomes evident from these comparative tests that surprisingly, theprocessability of the extruded mass can be improved by adjusting theratio of PEO to PEG.

EXAMPLE 8

In order to investigate if also multicarboxylic acids other than citricacid could hamper the formation of oxymorphone-N-oxide, tabletscontaining maleinic acid or fumaric acid were manufactured as describedin example 1. For comparison, also tablets containing the inorganic saltNaH₂PO₄ were manufactured. The samples were stored in open dishes at 40°C. and 75% relative humidity for 4 weeks.

The individual constituents of the extruded mixtures as well as thetotal amount of decomposition products before and after storage underaccelerated storage conditions are summarized in the table here below:

constituents (wt.-%) decomposition products (wt.-%) ex. (A) PEO PEG HPMCα-toc. further ingredient (wt.-%) oNo¹ oNo² Σ¹ Σ² J₁ 1.5 76.0 10.0 10.01.5 Maleinic acid 1.0% nd nd 0.20 0.22 J₂ 1.5 76.0 10.0 10.0 1.5 Fumaricacid 1.0% nd nd 0.17 0.30 J₃ 1.5 76.0 10.0 10.0 1.5 NaH₂PO₄ 1.0%* nd0.18 0.06 0.75 (A): oxymorphone hydrochloride PEO: polyethylene oxideM_(w) 7 mio g/mol PEG: polyethylene glycol 6000 HPMC: hypromellose100,000 Pa*s α-toc.: α-tocopherol *NaH₂PO₄: Used in form of 1.3% of thedi-hydrate oNo: oxymorphone-N-oxide (mixture) Σ: sum of all impurities;maleinic acid, fumaric acid and related compounds subtracted from sum ofimpurities ¹after extrusion, before storage ²after storage, open dish, 4weeks, 40° C., 75% rel. humidity

In case of maleinic and fumaric acid these compounds and for maleinicacid another related compound were detected during the purity tests asimpurities (up to about 40%). Their values have been subtracted from thesum of impurities.

It becomes evident from a comparison of examples J₁ and J₂ to A₁ and B₁that the presence of maleinic and fumaric acid protected oxymorphonetotally against oxidation to N-oxide and to a large extent against otherdegradation although the samples were stored in open dishes and not inclosed bottles. These results are comparable to those obtained withcitric acid (example 1, D₄ and E₂-E₄). Samples containing NaH₂PO₄ (J₃)exhibited protection against N-oxide formation and other degradationwhen compared to the formulations without any acidic compound (A₁ andB₁) but to a less extent than the multicarboxylic acids like citric,maleinic and fumaric acid.

EXAMPLE 9

In order to investigate if the presence of citric acid also protectsoxidation sensitive opioids other than oxymorphone against N-oxidation,tablets containing oxycodone hydrochloride were manufactured asdescribed in example 1.

For comparison, also tablets containing smaller amounts of α-tocopherolwere manufactured. The samples were stored in open dishes at 40° C. and75% relative humidity for 4 weeks.

The individual constituents of the extruded mixtures as well as thetotal amount of decomposition products before and after storage underaccelerated storage conditions are summarized in the table here below:

constituents (wt.-%) decomposition products (wt.-%) ex. (A) PEO PEG HPMCα-toc. further ingredient (wt.-%) oNo¹ oNo² Σ¹ Σ² K₁ 1.5 77.0 10.0 10.01.5 / 0.05 0.58 0.31 1.63 K₂ 1.5 78.3 10.0 10.0 0.2 / 0.05 0.28 0.580.69 K₃ 1.5 76.0 10.0 10.0 1.5 Citric acid 1.0 nd nd 0.19 0.22 K₄ 1.577.3 10.0 10.0 0.2 Citric acid 1.0 nd nd 0.18 0.23 (A): oxycodonehydrochloride PEO: polyethylene oxide M_(w) 7 mio g/mol PEG:polyethylene glycol 6000 HPMC: hypromellose 100,000 Pa*s α-toc.:α-tocopherol oNo: oxycodone-N-oxide Σ: sum of all impurities ¹afterextrusion, before storage ²after storage, open dish, 4 weeks, 40° C.,75% rel. humidity

These results show that citric acid protected oxycodone totally againstoxidation to the N-oxide and to a large extent against other degradationalthough the samples were stored in open dishes rather than in closedbottles. Reducing the amount of α-tocopherol resulted in reduceddegradation, when formulations were employed not containing citric acid.These results are comparable to those obtained with oxymorphone.

EXAMPLE 10

In accordance with Example 1, tablets containing tramadol HCL weremanufactured from the following compositions:

L₁ L₂ L₃ L₄ Tramadol HCl [%] 13.3 13.3 13.3 13.3 PEO [%] 61.0 61.7 61.261.5 PEG [%] 15.0 15.0 15.0 15.0 HPMC [%] 10.0 10.0 10.0 10.0a-tocopherol [%] 0.2 — — 0.2 Citric acid, anhydrous [%] 0.5 — 0.5 —Tablet weight [mg] 600 600 600 600 PEO:PEG 4.07:1 4.11:1 4.08:1 4.10:1

The dissolution profile of the tablets was investigated under thefollowing conditions: Paddle apparatus equipped with sinker, 75 rpm, 37°C., 600 mL simulated intestinal fluid pH 6.8 (phosphate buffer). Therelease profile of tramadol was detected spectrometrically at 271 nm.

The results are displayed in FIG. 1.

The tablets according to example L₂ show the fastest dissolution whichis about 20% faster than that of the slow releasing tablets according toexamples L₁ and L₄ after 480 minutes. The release from tablets accordingto L₃ is faster than those two batches, but still about 6% slower thanfrom tablets according to L₂ after 480 minutes.

This is surprising as a big influence of the presence of α-tocopherol onthe dissolution profile is observed. This particularly surprising giventhat the role of the α-tocopherol in the formulation is to act as anantioxidant for the prevention of polymer degradation. Interestingly thepresence of citric acid compensates for a small part of this effect.

EXAMPLE 11

By swelling of a tablet according to examples L₁ (Example 10) in anappropriate amount of water, a homogeneous gel was obtained.Accordingly, tablets according to examples L₂ to L₄ were swelled in thesame amount of water, i.e. under identical conditions, to obtain therespective gels. The viscosity of each gel was measured next as anindirect measure for the polymer chain length of the ethylene oxidecontained therein. The viscosity measurements were conducted by means ofa rotational viscometer at a shear rate of 40 s⁻¹.

α-Tocopherol Citric acid Viscosity (mPas) L₁ + + 381 L₂ − − 67 L₃ − +154 L₄ + − 337

Compared to the dissolution profiles of example 10, the same ranking wasobtained: The formulation according to example L₂ exhibited the lowestviscosity, while the formulations according to examples L₁ and L₄exhibited the highest viscosity. The formulation according to example L₃exhibited a significantly lower viscosity than the two high viscosityformulations but is still superior to formulation L₂.

The higher viscosity of the formulations L₁ and L₄ is an indication fora higher average polymer chain length of the polyethylene oxidecontained therein. Apparently, the polyethylene oxide contained informulations L₁ and L₄ has less been affected by oxidative degradationin the course of manufacture of the dosage form than formulations L₂ andL₃.

Summarizing the results of the dissolution profile (Example 10)measurements and the viscosity determinations, it can be concluded thatthe increase in dissolution velocity is based on more pronounced polymerdegradation during the manufacturing for the batches withoutα-tocopherol (examples L₂ and L₃).

These results show that acid (B), e.g. citric acid, also has aprotective effect on the polymer during manufacturing. Formulation L₃which does not contain any α-tocopherol but citric acid shows a higherviscosity and lower acceleration of dissolution in comparison to theformulation L₂ which contains neither α-tocopherol nor citric acid.

1. A tamper-resistant pharmaceutical dosage form in form of a tablethaving a breaking strength of at least 300 N thermoformed by hot-meltextrusion of a mixture comprising a pharmacologically active ingredient(A), a free physiologically acceptable multicarboxylic acid (B) in anamount of from 0.001 wt.-% to 5.0 wt.-%, based on the total weight ofthe pharmaceutical dosage form, an antioxidant selected from the groupconsisting of ascorbic acid or the salts thereof, ascorbylic palmitate,α-tocopherol, vitamin E-succinate, vitamin E-palmitate,butylhydroxyanisol, butylhydroxytoluene, monothioglycerine, coniferylbenzoate, nordihydroguajaretic acid, gallus acid esters, phosphoricacid, and sodium bisulphite; in an amount of from 0.001 wt.-% to 5.0wt.-%, based on the total weight of the pharmaceutical dosage form; anda polyalkylene oxide (C) having a weight average molecular weight M_(w)of at least 200,000 g/mol.
 2. The pharmaceutical dosage form accordingto claim 1, wherein the pharmacologically active ingredient (A) is anopioid.
 3. The pharmaceutical dosage form according to claim 1, whereinthe multicarboxylic acid is selected from the group consisting of maleicacid, fumaric acid, glutaric acid, malonic acid and citric acid.
 4. Thepharmaceutical dosage form according to claim 1, wherein the content ofthe acid (B) is within the range of from 0.005 to 2.5 wt.-%, based onthe total weight of the pharmaceutical dosage form.
 5. Thepharmaceutical dosage form according to claim 1, wherein the antioxidantis α-tocopherol.
 6. The pharmaceutical dosage form according to claim 1,wherein after storage for 4 weeks at 40° C. and 75% rel. humidity, thecontent of pharmacologically active ingredient (A) amounts to at least98.0% of its original content before storage.
 7. The pharmaceuticaldosage form according to claim 1, wherein after storage for 4 weeks at40° C. and 75% rel. humidity, the content of the polyethylene oxide (C)amounts to at least 98.0% of its original content before storage.
 8. Thepharmaceutical dosage form according to claim 1, wherein thepharmacologically active ingredient (A) is embedded in a matrixcomprising the polyalkylene oxide (C), said matrix controlling therelease of the pharmacologically active ingredient (A) from thepharmaceutical dosage form.
 9. The pharmaceutical dosage form accordingto claim 1, wherein the pharmacologically active ingredient (A) isselected from the group consisting of oxymorphone, oxycodone,hydromorphone, and the physiologically acceptable salts thereof.
 10. Thepharmaceutical dosage form according to claim 1, wherein the relativeweight ratio of the polyalkylene oxide (C) to the pharmacologicallyactive ingredient (A) is at least 1:1.
 11. The pharmaceutical dosageform according to claim 1, which is adapted for administration oncedaily or twice daily.
 12. The pharmaceutical dosage form according toclaim 1, which has a breaking strength of at least 500 N.
 13. Apackaging containing a pharmaceutical dosage form according to claim 1and an oxygen scavenger.
 14. A process for the production of thepharmaceutical dosage form according to claim 1 comprising the steps: a)mixing all components to form a resultant mixture; b) heating theresultant mixture in an extruder at least up to the softening point ofthe polyalkylene oxide (C) and extruding extrudate through the outletorifice of the extruder by application of force, c) singulating thestill plastic extrudate and forming into the pharmaceutical dosage formor d) cooling and optionally reheating the singulated extrudate andforming it into the pharmaceutical dosage form.
 15. A method of treatingpain in a patient in need of such treatment, said method comprisingadministering to said patient a pharmaceutical dosage form according toclaim 1.